RP#094
Case# Katagiri094, Male, Japanese
CasePresentingHPOs HP:0007987, HP:0007675, HP:0000551, HP:0007737
CaseMethod1 WES
CaseMethod2 Sanger
CaseGenotypingMethod PCR of exons 4-11 of CNGA1
Variant NM_000087.3(CNGA1):c.265delC (p.Leu89Phefs)
ClinVar 225315 link
gnomAD 0.001378 link
RP#029
Case# Katagiri029, female, Japanese
CasePresentingHPOs HP:0007987, HP:0007675, HP:0000551, HP:0007737
CaseMethod1 WES
CaseMethod2 Sanger
CaseGenotypingMethod PCR of exons 4-11 of CNGA1
Variant NM_000087.3(CNGA1):c.265delC (p.Leu89Phefs)
ClinVar 225315 link
gnomAD 0.001378 link
1
Case1: Female, 45 yrs report
CasePresentingHPOs: HP:0008994, HP:0002015, HP:0003236, HP:0003273, HP:0031237, HP:0003555, HP:0100295, HP:0012548 (Proximal muscle weakness in lower limbs, Dysphagia, Elevated serum creatine phosphokinase, Hip contracture, Internally nucleated skeletal muscle fibers, Fiber splitting, Muscle fiber atrophy, Skeletal muscle fatty infiltration)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: Proband of Family 1, Mother of Case 2, Variant is de novo
CasePreviousTesting: N/A
CaseGenotypingMethod: The TPM2 gene was sequenced and variants identified. No other information is provided.
Variant: NM_003289.3:c.14_16delAGA (p.Lys7del)
ClinVar: 140486 https://www.ncbi.nlm.nih.gov/clinvar/variation/140486/
gnomAD: Not in gnomAD
These results suggest that expression of CASQ2R33Q enhances the propensity for spontaneous Ca2+ release from the SR, apparently by increasing the functional activity of the RyR2 channels.
NonPatientCell myocardium, UBERON:0002349
GeneAlteration isolated adult rat ventricular myocytes infected with adenoviruses for expression of either the wild-type (WT) or mutant forms of CASQ2. Cytosolic and intra-SR [Ca2+]
FunctionalEvidence Causes leakage of Ca2+ transients from SR (fig. 5)
FAVariants NM_001232.3(CASQ2):c.97C>T (p.Arg33Ter), 41043 link
F3-II
Case# F3-II1, female, 23yo report, Greek
CasePresentingHPOs HP:0008947, HP:0003155, HP:0010837, HP:0003124, HP:0003141, HP:0012347, HP:0012358, HP:0001263 (Infantile Hypotonia, Elevated alkaline phosphatase, Low ceruloplasmin, Elevated cholesterol, Elevated LDL-C, Abnormla N-glycosylation, Abnormal O-glycosylation, Psychomotor delay)
HPOsFreeText Elevated amino transferases
CaseNotHPOs n/a
CasePreviousTesting Serum ALT 36–172 U/l [normal range, 0–50 U/l], AST 31–119 U/l [normal range, 0–50 U/l], ALP 132–1,528 U/l [normal range, < 360 U/l], ceruloplasmin 17–24 mg/dl [normal range, 15–60 mg/dl], cholesterol 231–257 mg/dl [normal range, 120–200 mg/dl], LDL-C 161–171 mg/dl [normal range, 50–130 mg/dl], type 2 CDG
CaseMethod1 Sanger
CaseMethod2 n/a
CaseGenotypingMethod Sanger on patient and parents found variant in heterozygous state in both parents
Variant NM_152464.2(TMEM199):c.92G>C (p.Arg31Pro), homozygous
ClinVar 218964
gnomAD 0.00008933(Latino), 0.00004108(Overall), 10 heterozygotes
VariantEvidence n/a
CaseAddInfo nonconsanguineous
CasePMIDs n/a
F2-II2
Case# F2-II2, male, 41yo report
CasePresentingHPOs HP:0003155, HP:0010837, HP:0003124, HP:0001397, HP:0025321, HP:0003141, HP:0012347, HP:0006579, HP:0000023, HP:0003236 (Elevated alkaline phosphatase, Low ceruloplasmin, Elevated cholesterol, Steatosis, Copper accumulation in liver, Elevated LDL-C, Abnormal N-glycosylation, Neonatal jaundice, Inguinal hernia, Elevated CPK)
HPOsFreeText Inguinal hernia and increased CPK (11yo) minimal fibrosis (30yo), elevated amino transferases (11yo)
CaseNotHPOs HP:0200032 ( Kayser-Fleischer rings)
CasePreviousTesting serum ALT 190 U/l [normal range, 0–50 U/l], AST 153 U/l [normal range, 0–50 U/l], and ALP 718 U/l [normal range, < 360 U/l] (11yo), hepatic dry copper weight of 90 μg/g [normal range, <40 μg/g], ceruloplasmin 8.8 mg/dl [normal range, 15–60 mg/dl], cholesterol 204–337 mg/dl [normal range, 120–200 mg/dl], LDL-C 182–226 mg/dl [normal range, 50–130 mg/dl], type 2 CDG.
19067230: Laboratory tests excluded celiac disease, alpha1-antitrypsin deficiency, cystic fibrosis, galactosaemia and hypobetalipoproteinaemia. Liver iron concentration was normal, normal saturation of transferrin and ferriten, negative for hepatotrophic viruses. Serum anithrombin III (57%, normal range 80–120%) and clotting factor XI (42% , normal range 60–140%) were low.
CaseMethod1 WES
CaseMethod2 n/a
CaseGenotypingMethod WES in patient, sequenced father and mother found to be heterozygous for either variant
Variant NM_152464.2(TMEM199):c.[376-1G>A];[40G>C]
ClinVar 427819
gnomAD n/a for both
VariantEvidence Fig 2C, Western blot: reduced TMEM199 expression in patient fibroblasts
CaseAddInfo nonconsanguineous, father had history of hypercholesterolemia and ischemic heart disease.
CasePMIDs 19067230
F1-II2 and F1-II3
Family#PresentingHPOs HP:0003155, HP:0010837, HP:0003124, HP:0001397, HP:0010836, HP:0003141, HP:0012347, HP:0012358, HP:0001976 (Elevated alkaline phosphatase, Low ceruloplasmin, Elevated cholesterol, Steatosis, Abnormality of copper homeostasis, Elevated LDL-C, Abnormal N-glycosylation, Abnormal O-glycosylation, Reduced antithrombin III activity)
HPOsFreeText Elevated amino transferases, minimal fibrosis, slightly decreased coagulation factors XI, XIII, and antithrombin-III
FamilyNotHPOs HP:0200032 (Kayser-Fleischer rings)
CountryOrigin n/a
Ethnicity Greek
Race n/a
Family#PreviousTesting Metabolic work up and anyalysis of coagulation factors, the latter of which showed decreased antithrombin-II, factor XI, factor XIII, and protein S, type 2 CDG. No mutations found in ATP7B, Wilson's disease excluded.
Family#Method1 WES
Family#Method2 Sanger
Family#GenotypingMethod WES on siblings, confirmed heterozygous in parents with Sanger
Affected 2
Unaffected 2
Segregations n/a
PublishedLOD n/a
eLOD n/a
AddSegregationInfo consanguineous
ProbandLabel F1-II2, male, 14yo report
Case1PreviousTesting Serum ALT 54 U/l [normal range, 0–50 U/l], AST 73 U/l [normal range, 0–50 U/l], ALP 745 U/l [normal range, < 360 U/l], ceruloplasmin 11.5 mg/dl [normal range, 15–60 mg/dl], urine copper/creatine ratio 86.9 μg/g [normal range, < 60 μg/g], cholesterol 253 mg/dl [normal range, 120–200 mg/dl], LDL cholesterol 188 mg/dl [normal range, 50–130 mg/dl]
Case2 F1-II3, male, 6yo report
Case2PreviousTesting ALT 210 U/l [normal range, 0–50 U/l], AST 246 U/l [normal range, 0–50 U/l], ALP 1162 U/l [normal range, < 360 U/l], ceruloplasmin 15.6 mg/dl [normal range, 15–60 mg/dl], urine copper/creatine ratio 72.8 μg/g [normal range, < 60 μg/g], cholesterol 336 mg/dl [normal range, 120–200 mg/dl], LDL cholesterol 277 mg/dl [normal range, 50–130 mg/dl]
Variant NM_152464.2(TMEM199):c.20C>A (p.Ala7Glu), homozygous
ClinVar 218965
gnomAD 23 total heterozygotes (sampled from ~242458) for missense changes at this locus, no entry for this particular variant
Variant Evidence Fig 2C, Western blot: reduced TMEM199 expression in patient fibroblasts
FamilyAddInfo n/a
FamilyPMIDs n/a
Figure 1
Family#PresentingHPOs HP:0031317, HP:0011663
FamilyNotHPOs HP:0001635
CountryOrigin Newfoundland
Ethnicity NonHispanic/Latino
Race White
Family#PreviousTesting No
Family#GenotypingMethod Bidirectional resequencing
ClinVar NM_024334.2(TMEM43):c.1073C>T (p.Ser358Leu), ClinVarID: 734
FamilyPMIDs 3386698
Family 1
FamilyLabel UM Family 1
FamilyUM1PresentingHPOs n/a
FamilyNotHPOs n/a
CountryOrigin n/a
Ethnicity n/a
Race n/a
FamilyUM1PreviousTesting Screened nonsense and missense variants in 202 candidate genes comprising ~15.5Mb. Established evidence of linkage of 17q21-22.
Affected 4
Unaffected 0
Segregations n/a
PublishedLOD n/a
eLOD n/a
AddSegregationInfo One female typed positive(cannot have prostate cancer), one male typed positive(has other cancer)
ProbandLabel UM1 III-9, Male, 50
CasePresentingHPOs HP:0012125 (Prostate Cancer)
Variant NM_006361.5(HOXB13):c.251G>A (p.Gly84Glu)
ClinVar 128031
CAID n/a
gnomAD MAF=0.007574(European(Finnish)), 2 homozygotes
FamilyAddInfo ages rounded to nearest 5 year interval
FamilyPMIDs 17120048
compound heterozygous ACPT mutations were identified in family 6
Family Name: Family 6
FamilyPresentingHPOs: HP:0000705
FamilyNotHPOs:
CountryOrigin: Turkey
Ethnicity: Turkish
Race: n/a
FamilyPreviousTesting: candidate gene sequencing, array comparative genomic hybridization, or exome sequencing
FamilyGenotypingMethod: WES
Affected: 2
Unaffected: 3
Segregations: 1
PublishedLOD: n/a
eLOD: 1.0
AddSegregationInfo: non-consanguineous family
ProbandLabel: Family 6: III:1, female, 11 yo
Variant 1: NM_033068.2(ACP4):c.382G>C (p.Ala128Pro)
ClinVar or CAID: 374865, https://www.ncbi.nlm.nih.gov/clinvar/variation/374865/
genomAD: 2.449e-5, http://gnomad.broadinstitute.org/variant/19-51294991-G-C
Variant 2: NM_033068.2(ACP4):c.397G>A (p.Glu133Lys)
ClinVar: 374866, https://www.ncbi.nlm.nih.gov/clinvar/variation/374866/
genomAD: 8.196e-6, http://gnomad.broadinstitute.org/variant/19-51295006-G-A
FamilyAddInfo: parents unaffected
CasePresentingHPOs: HP:0006297, HP:0011077, HP:0000698
CasePresentingHPOTerm: hypoplastic enamel, destructed first molars, mandibular anterior teeth had incisal edges,
CaseNotHPOs: HP:0011073
AddCaseInfo: compound heterozygous mutations
VariantEvidence:
Case 19
Case19 Male, Finland
CasePresentingHPOs HP:0000347, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260
(Micrognathia, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Type II lissencephaly)
HPOsFreeText Crown-heel body length 49cm, body weight 3864g, brain weight 286g, abnormal larynx/trachea, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, leptomeningeal heterotopia, neuroepithelial rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus, (Fig6:) markedly narrowed basis pontis with minute corticospinal tract and a larger tg above, dysplastic dentate nucleus with irregular neuronal strands and intermingled matrix-like small cells is seen in the cerebellar hilus
CaseNotHPOs HP:0001161, HP:0001829, HP:0001627, HP:0000157, HP:0007165
(Hand polydactyly, Foot polydactyly, Congenital heart defect, Tongue abnormality, Periventricular neuronal heterotopia)
NotHPOsFreeText Uterus duplex, hydranencephaly/anencephaly, true alobar or semilobar holoprosencephaly
CasePreviousTesting n/a
Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous
ClinVar 1143
gnomAD MAF= 0.009594(European(Finnish)), no homozygotes
CaseAddInfo died 1 minute after birth, 40+6wk gestational age
CasePMIDs n/a
As summarized in Table 2, the JPH2 genotype positive subjects were diagnosed with HCM at 27, 24 and 30 years with septal wall thicknesses of 22, 38 and 18 mm for each mutation respectively
Case 3: Female, diagnosed at 30 yrs, 18mm septal wall thickness, no mutations in HCM associated genes, no family history
HP:0002094, HP:0006689, (dyspnea, bacterial endocarditis)
Variant: NM_020433.4(JPH2):c.494C>T (p.Ser165Phe),
ClinVar ID: 30457
https://www.ncbi.nlm.nih.gov/clinvar/variation/30457/
not in ExAC
One mutation
Case44: Female, 7 yrs onset
CasePresentingHPOs: HP:0006785, HP:0003236, HP:0040083, HP:0003307, HP:0002527, HP:0003701, HP:0003323, HP:0009042, HP:0003458, HP:0100305, HP:0031542 (Limb-girdle muscular dystrophy, Elevated serum creatine kinase, Toe walking, Hyperlordosis, Falls, Proximal muscle weakness, Progressive muscle weakness, Marked muscular hypertrophy, EMG: myopathic abnormalities, Ring fibers, Myelin-like whorls in vacuolated fibers)
HPOsFreeText: Wheelchair at 14 yrs
CaseNotHPOs: HP:0003115, HP:0100543 (Abnormal EKG, Cognitive impairment)
NotHPOsFreeText: N/A
CaseAddInfo: Proband is homozygous for this duplication, Parents are confirmed heterozygous
CasePreviousTesting: Peak CPK at 20,000 IU/l, Partially absent α- and β-sarcoglycan staining, Normal dystrophin content, Totally absent γ-sarcoglycan staining
CaseGenotypingMethod: Total mRNA was isolated from muscle biopsies and cDNA was synthesized from it via reverse transcriptase. PCR and SSCP analysis was performed and excised, amplified, and sequenced. After finding the mutations, DNA from peripheral blood leukocytes or muscle biposies was isolated, PCR amplified, and sequenced to confirm the results.
Variant: NM_000231.2(SGCG):c.87dup (p.Gly30fs)
ClinVar: 2008 https://www.ncbi.nlm.nih.gov/clinvar/variation/2008/
gnomAD: 0.000008805, https://gnomad.broadinstitute.org/variant/13-23777919-A-AT
the famil
Family1: N/A
FamilyPresentingHPOs: HP:0009027, HP:0031374, HP:0008963, HP:0001761, HP:0012515, HP:0008944, HP:0008948, HP:0003484, HP:0001265, HP:0003458 (Foot dorsiflexor weakness, Ankle weakness, Tibialis muscle weakness, Pes cavus, Hip flexor weakness, Distal lower limb amyotrophy, Proximal upper limb amyotrophy, Upper limb muscle weakness, Hyporeflexia, EMG: myopathic abnormalities)
HPOsFreeText: N/A
FamilyNotHPOs: HP:0009130, HP:0003474, HP:0003445 (Hand muscle atrophy, Sensory impairment, EMG: neuropathic changes)
NotHPOsFreeText: N/A
FamilyPreviousTesting: Genomic DNA was extracted and RFLP was performed on all family members. Fragments were separated, hybridized, and subject to linkage analysis.
FamilyGenotypingMethod: A refined linkage analysis was performed with the deaths of some family members and additions of others, allowing for the narrowing of the genomic region. Afterwards, RNA was extracted from a frozen sample of the proband and cDNA was sequenced. PCR amplification and direct sequencing was used to confirm the mutation in the proband. SSCP was used to screen the family members and other NM probands for the mutation.
FamilyAddInfo: Pedigree in Figure 1
FamilyPMIDs: 1347195 (Family Characterization)
Affected: 9 Alive, 2 Now deceased
Unaffected: 11
Segregations: 10
PublishedLOD: 4.52 at zero recombination with candidate gene sequencing
AddSegregationInfo: Annotate with other pertinent information as needed.
ProbandLabel: IV-3
Variant: NM_152263.4(TPM3):c.26T>G (p.Met9Arg)
ClinVar: 12446 https://www.ncbi.nlm.nih.gov/clinvar/variation/12446/
gnomAD: European (Non-Finnish) 8.828e-6, Overall 4.009e-6 https://gnomad.broadinstitute.org/variant/1-154164469-AT-A
individual lII-12
Case# Monnier 3:12, died age 30, male, French
CasePresentingHPOs HP:0001649, HP:0006682, HP:0012416, HP:0001695, HP:0001945
CasePreviousTesting N/A
CaseMethod1 PCR
CaseGenotypingMethod PCR and sequencing gel for CACNL1A3.PCR1 amplimer
Variant NM_000069.2(CACNA1S):c.3257G>A (p.Arg1086His)
ClinVar 17626
gnomAD 0.00002978 link
VariantEvidence N/A
Table 1,
Case#: 1
Variant: homozygous NM_014495.3:c.286_288del (ANGPTL3) p.Glu96del ← listed in Allele Registry, but paper lists it as p.Glu95del
ClinVar: not in ClinVar
gnomAD: total allele count: 42, allele frequency for African population with an allele count of 16: 0.0006458
Case#: 2
Variant: homozygous NM_014495.3(ANGPTL3):c.439_442del (p.Asn147Terfs)
CAId: CA145485
ClinVar: 91865
gnomAD: 37 allele count, 0.0001966 allele frequency for European with allele count of 23
Case#: 3 (previously report in PMID 20942659)
Variant: compound heterozygous NM_014495.3(ANGPTL3):c.385G>T (p.Glu129Ter) and NM_014495.3(ANGPTL3):c.50_51delCCinsGA (p.Ser17Ter)
ClinVar: 18439 (p.Ser17Ter), 18440 (p.Glu129Ter), for both variants - 1 assertion for pathogenic based on OMIM but no assertion criteria provided
gnomAD: not in gnomAD
Case#: 4
Variant: compound heterozygous NM_014495.3(ANGPTL3):c.439_442del (p.Asn147Terfs) and NM_014495.3(ANGPTL3):c.883T>C (p.Phe295Leu)
ClinVar: 91865 and 91867
gnomAD: not in gnomAD
Case#: 5
Variant: heterozygous c.355_360delAACT
ClinVar: not in ClinVar
CAId: none
gnomAD: not in gnomAD
Case#: 6
Variant: heterozygous c.62 insCTCAT
ClinVar: not in ClinVar
CAId: none
gnomAD: not in gnomAD
Case#: 7
Variant: heterozygous NM_014495.3:c.167G>T (ANGPTL3)
ClinVar: not in ClinVar
CAId: CA340600195
gnomAD: not in gnomAD
Case#: 8
Variant: heterozygous NM_014495.3:c.995G>A
CAID: CA886769
ClinVar: not in ClinVar
gnomAD: 0.0001476 total allele freq, 37 allele count, 0.0008191 is largest allele freq for Other population with allele count of 5
Case#: Consequence 11 Table 1 in Data Supplement (4 cases)
DiseaseAssertion: HCM
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3
CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing
Variant: NM_000257.4(MYH7):c.2779G>A (p.Glu927Lys)
ClinVar: 42932 https://www.ncbi.nlm.nih.gov/clinvar/variation/42932/
CAID: n/a
gnomAD: absent
CaseMYH7-17: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: 3 other probands share this genotype
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.1750G>C (p.Gly584Arg)
ClinVar: 14090 https://www.ncbi.nlm.nih.gov/clinvar/variation/14090/
gnomAD: European (Non-Finnish) 8.790e-6, Overall 3.976e-6 https://gnomad.broadinstitute.org/variant/14-23896932-C-G
CaseMYH7-14: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.2167C>T (p.Arg723Cys)
ClinVar: 14095 https://www.ncbi.nlm.nih.gov/clinvar/variation/14095/
gnomAD: South Asian 3.266e-5, Overall 1.194e-5 https://gnomad.broadinstitute.org/variant/14-23895023-G-A
CaseMYH7-3: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: 3 other probands share this genotype
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.2717A>G (p.Asp906Gly)
ClinVar: 14125 https://www.ncbi.nlm.nih.gov/clinvar/variation/14125/
gnomAD: European (Non-Finnish) 8.792e-6, Overall 3.977e-6 https://gnomad.broadinstitute.org/variant/14-23893321-T-C
CaseMYH7-23: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.1357C>T (p.Arg453Cys)
ClinVar: 14089 https://www.ncbi.nlm.nih.gov/clinvar/variation/14089/
gnomAD: Not in gnomAD
c.3007_3337del
Variant NM_144668.5:c.3007_3337del
ClinVar 586974
family A, only 2 of 37 candidate variants segregated with the disease in the family (Table 2 and Table S3). These two mutations were homozygous missense mutations in EXTL3 (c.1537C>T [p.Arg513Cys] [GenBank: NM_001440.3]) and CHST9 (MIM: 610191; c.1133A>G [p.Asn378Ser] [GenBank: NM_031422]) (Figure 2B)
Family A autosomal recessive variant found in CHST9 (MIM: 610191; c.1133A>G [p.Asn378Ser] [GenBank: NM_031422])
Case 2
Case2: Female, Birth onset
CasePresentingHPOs: HP:0002093, HP:0002938, HP:0002015, HP:0003798, HP:0003200, HP:0003548 (Respiratory insufficiency, Lumbar hyperlordosis, Dysphagia, Nemaline bodies, Ragged-red fibers, Subsarcolemmal accumulations of abnormally shaped mitochondria)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: Mother of proband
CasePreviousTesting: N/A
CaseGenotypingMethod: See Family
Variant: NM_003289.3:c.397C>T (p.Arg133Trp)
ClinVar: 12463 https://www.ncbi.nlm.nih.gov/clinvar/variation/12463/
gnomAD: Not in gnomAD
Case 1
Case1: Female, Birth onset
CasePresentingHPOs: HP:0008947, HP:0008872, HP:0002033, HP:0030043, HP:0001349, HP:0001488, HP:0010804, HP:0002650 (Infantile hypotonia, Feeding difficulties in infancy, Poor suck, Hip subluxation, Facial diplegia, Bilateral ptosis, Tented mouth, Scoliosis)
HPOsFreeText:Disorganized myofibrils and thickened Z bands
CaseNotHPOs: HP:0003798 (Nemaline bodies)
NotHPOsFreeText: N/A
CaseAddInfo: Proband of Family 1
CasePreviousTesting: N/A
CaseGenotypingMethod: See Family
Variant: NM_003289.3:c.397C>T (p.Arg133Trp)
ClinVar: 12463 https://www.ncbi.nlm.nih.gov/clinvar/variation/12463/
gnomAD: Not in gnomAD
The older sibling, individual 1 (III-1)
Case#: Family 1, Individual III-1, Female, 27 yo, dx at 3 months old
CasePresentingHPOs: HP:0000639, HP:0001332, HP:0001270, HP:0002497, HP:0001272, HP:0002062, HP:0000571, HP:0002540, HP:0000511, HP:0012547, HP:0001260, HP:0030187, HP:0001332, HP:0000473
CaseNotHPOs: HP:0003474, HP:0007108
CasePreviousTesting: MRI showing brain hypomyelination
CaseGenotypingMethod: combination of homozygosity mapping and WES, haplotype analysis
Variant: NM_177400.2(NKX6-2):c.121A>T (p.Lys41Ter)
ClinVar: 430622, https://www.ncbi.nlm.nih.gov/clinvar/variation/430622/
gnomAD: n/a
VariantEvidence:
CaseAddInfo: Wheelchair bound at 27 yo
CasePMIDs:
PatientID: IV-13
KindredID: 2
Case: F, Age Unknown, German
DiseaseAssertion: VHL (Asymptomatic)
FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0005584; HP:0002666 (Renal cell carcinoma, Pheochromocytoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 7759077
SupplementalData: N/A
Variant: p.Y98H (c.292T>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2223, https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/
CAID: N/A
gnomAD: 0.00001343, https://gnomad.broadinstitute.org/variant/3-10183823-T-C
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: Y98H (c.292T>C)
MultipleGeneVariants: N/A
PatientID: V-12
KindredID: 2
Case: M, Age Unknown, German
DiseaseAssertion: VHL (Asymptomatic)
FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0005584; HP:0002666 (Renal cell carcinoma, Pheochromocytoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 7759077
SupplementalData: N/A
Variant: p.Y98H (c.292T>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2223, https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/
CAID: N/A
gnomAD: 0.00001343, https://gnomad.broadinstitute.org/variant/3-10183823-T-C
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: Y98H (c.292T>C)
MultipleGeneVariants: N/A
PatientID: None
KindredID: 7
Case: F, 13Y0M, Ethnicity unknown
DiseaseAssertion: pheochromocytoma
FamilyInfo: No familial/syndromic (FS) association
CasePresentingHPOs: HP:0002666 (pheochromocytoma)
CaseHPOFreeText: Benign bilateral pheochromocytoma at age 13 Y
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: SDHB,SDHC, SDHD, and exons 10, 11, 13, 14, 15 and 16 of RET proto-oncogene
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167Q (c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVar: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A
VariantEvidence:N/A
MutationType: missense_variant;transition
CivicName: R167Q (c.500G>A)
MultipleGeneVariants: N/A
PatientID: None
KindredID: 6
Case: F, 18Y0M, Ethnicity unknown
DiseaseAssertion: assumed VHL
FamilyInfo: Familial/syndromic (FS) association
CasePresentingHPOs: HP:0002666; HP:0002668; HP:0010797; HP:0030405 (Pheochromocytoma; paraganglioma; hemangioblastoma; pancreatic endocrine tumor)
CaseHPOFreeText: Benign bilateral pheochromocytoma and sympathetic PGL, CNS hemangioblastoma and PNET at age 18
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: SDHB,SDHC, SDHD, and exons 10, 11, 13, 14, 15 and 16 of RET proto-oncogene
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167W (c.499C>T)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 2218 https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: N/A
gnomAD: 0.000007954 https://gnomad.broadinstitute.org/variant/3-10191506-C-T
VariantEvidence: N/A
MutationType: missense_variant; transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
In 1996, we described a 3 generation VHL 2A kindred with 11 mutation carriers. We aim to share our experience regarding the long-term follow-up of this family
PatientID: 26
KindredID: 1
Case: M, 16Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: This patient was a member of family 1, where 14/32 total patients were diagnosed with VHL. One of which (I-32) was a mutational carrier with down syndrome. The other 13 patients had varying phenotypes, including adrenal pheochromocytoma, pancreatic endocrine tumors, liver and bone metastases, paraganglioma, cerebellar, spinal, and retinal hemangioblastomas, polycythemia, and chondrosarcoma. See Fig. 1 for family pedigree.
CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)
CaseHPOFreeText: Patient presented with his initial VHL-related clinical manifestations at 16Y0M. She had adrenal pheochromocytoma and diagnosed with VHL subtype 2A (see table 1).
CaseNotHPOs: HP:0002668 (paraganglioma)
CaseNotHPOFreeText: Patient does not have paraganglioma.
CasePreviousTesting: N/A
PreviouslyPublished: 8550742
SupplementalData: N/A
Variant: p.V166F (c.496G>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transversion
CivicName: V166F (c.496G>T)
MultipleGeneVariants: N/A
16 different families
PatientID: 1
KindredID: 5
Case: M, 19Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: Patient had 3 carrier children of this mutation, without any further phenotypic information.
CasePresentingHPOs: HP:0005584; HP:0000107; HP:0006748; HP:0009713; HP:0001737; HP:0030939; HP:0100684 (renal cell carcinoma, renal cysts, adrenal pheochromocytoma, spinal hemangioblastoma, pancreatic cysts, endolymphatic sac tumor, salivary gland neoplasm)
CaseHPOFreeText: Patient presented with renal cell carcinoma, renal cysts, adrenal pheochromocytoma, spinal hemangioblastoma, pancreatic cysts, endolymphatic sac tumor and salivary gland neoplasm at age 19Y0M. Patient was diagnosed with VHL type 1 (see table 2).
CaseNotHPOs: HP:0002668; HP:0030405 (paraganglioma; pancreatic endocrine tumor)
CaseNotHPOFreeText: Patient negative for paraganglioma and pancreatic endocrine tumor.
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.G93R (c.277G>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 223174, https://www.ncbi.nlm.nih.gov/clinvar/variation/223174
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant, transversion
CivicName: G93R (c.277G>C)
MultipleGeneVariants: N/A
16 different families
PatientID: X-I
KindredID: 10
Case: M, 28Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: No family history reported.
CasePresentingHPOs: HP:0010797; HP:0006880; HP:0009711; HP:0009713; HP:0001737 (hemangioblastoma, cerebellar hemangioblastoma, retinal capillary hemangioma, spinal hemangioblastoma, pancreatic cyst)
CaseHPOFreeText: Patient presented with CNS, spinal, retinal and cerebellar hemangioblastoma, as well as a pancreatic cyst at age 28Y0M and was diagnosed with VHL type 2A (see table 2).
CaseNotHPOs: HP:0000107; HP:0005584; HP:0006748; HP:0002668; HP:0030405 (renal cyst; renal cell carcinoma; adrenal pheochromocytoma; paraganglioma; pancreatic endocrine tumor)
CaseNotHPOFreeText: Patient negative for renal cyst, renal cell carcinoma, adrenal pheochromocytoma, paraganglioma, and pancreatic endocrine tumor.
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: partial deletion (<1kb)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: partial_deletion
CivicName: NULL (partial deletion)
MultipleGeneVariants: N/A
Case 7In 1980, a 15-yr-old girl with a familial history of VHL presented with loss of visual acuity leading to the diagnosis of bilateral retinal hemangioblastomas followed by laser and cryotherapy. However, outcome was unilateral blindness. Furthermore, the patient was then operated three times for CNS hemangioblastomas between ages 18 and 24. At age 26, she presented with a palpable lateral neck mass. CT of the head and neck revealed a 3-cm carotid body tumor. The tumor was removed, and histology showed a paraganglioma. Molecular genetics identified the VHL germline mutation p.Thr105Pro.
PatientID: 7
KindredID: 7
Case: F, 26Y0M, Ethnicity Unknown
DiseaseAssertion: assumed VHL
FamilyInfo: Positive family history of VHL.
CohortInfo: An international consortium registered patients with head and neck paragangliomas with VHL or RET gene mutations.
CasePresentingHPOs: HP:0000618; HP:0009711; HP:0010797; HP:0002668 (blindness, retinal capillary hemangioma, hemangioblastoma, paraganglioma)
CaseHPOFreeText: At 15Y she presented with loss of visual acuity, leading to the diagnosis of bilateral retinal hemangioblastomas (treated with laser and cryotherapy), with the outcome of unilateral blindness. The patient was then operated 3 times for CNS hemangioblastomas between ages 18 and 24. At age 26, she presented with a palpable lateral neck mass. CT of the head and neck revealed a 3-cm carotid body tumor (paraganglioma).
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: RET
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.T105P (c.313A>C)
LegacyVariant: p.T105P
CaseProblemVariantFreeText: As the publication only provides the p., the mutation was deduced to p.T105P (c.313A>C)
ClinVarID: 496055 https://www.ncbi.nlm.nih.gov/clinvar/variation/496055/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transversion
CivicName: T105P (c.313A>C)
MultipleGeneVariants: N/A
VHL p.Ser139fs
An international consortium of registered patients with head and neck paragangliomas with VHL or RET gene mutations were analyzed. Eleven of the 12 patients were found to carry germline mutations in theVHL gene. Blood was used for molecular genetic analyses and the NM_000551.2 reference sequence was used. The 26 year old female proband was found to harbour the p.Ser139fs mutation of the VHL gene. She had a family history of VHL and presented with lumbar pain. CT showed a right adrenal pheochromocytoma that was removed. Two years later, she had left nephrectomy for multiple renal cell carcinoma. At age 33, she presented with a lateral cervical mass associated with Horner’s syndrome and pain in the right ear. CT showed a 6cm carotid paraganglioma that was removed and histologically confirmed. At age 42, a cerebellar hemangioblastoma was removed. As the publication only provides the p., the mutation p.Ser139fs was not able to be matched to the exact mutation.
c.499C > T1 (1%)2a/b43HBr, HBsc, RCC, Pheo, Cr
PatientID: None
KindredID: 13
Case: Sex Unknown, 43Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CohortInfo: All VHL mutation carriers of 18 years or older who underwent surveillance according to Dutch VHL guidelines between 1972 and 2012 in the VHL expertise centers University Medical Center Groningen (UMCG) and University Medical Center Utrecht (UMCU) were included. Patients with VHL-disease subtype 2C (pheochromocytoma only) were excluded.
CasePresentingHPOs: HP:0009711; HP:0009713; HP:0005584; HP:0000107; HP:0002666 (Retinal capillary hemangioma, Spinal hemangioblastoma, Renal cell carcinoma, Renal cyst, Pheochromocytoma)
CaseHPOFreeText: VHL Type 2a/b.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 24132471
SupplementalData: Table 1
Variant: p.R167W (c.499C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: N/A
gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
SisExon 1 DeletionAsy––––––
PatientID: None
KindredID: 16
Case: F, Age Unknown, Chinese
DiseaseAssertion:Asymptomatic
FamilyInfo: Positive. The patient's sibling was the proband and presented with hemangioblastoma, renal cell carcinoma, and abnormality of the pancreas. Her niece also had the mutation but was asymptomatic. Another member of her family also had this mutation and was asymptomatic.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0010797, HP:0009711, HP:0002666, HP:0005584, HP:0001732 (hemangioblastoma, retinal capillary hemangioma, pheochromocytoma, renal cell carcinoma, abnormality of the pancreas)
CaseNotHPOFreeText: The patient did not present with epididymal or ovarian cystadenomas.
CasePreviousTesting: N/A
PreviouslyPublished:29330336
Variant: Exon 1 deletion
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVar: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: exon_loss_variant
CivicName: Exon 1 Deletion
MultipleGeneVariants: N/A
PatientID: 1
KindredID: 1
Case: 30Y0M, Sex and Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: Recorded as a familial tumor; no other family info present
CasePresentingHPOs: HP:0002666 (Pheochromocytoma)
CaseHPOFreeText: Bilateral pheochromocytoma reported with an age at diagnosis of 30 years of age.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: RET, SDHB/SDHC/SDHD
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167W (c.499C>G)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 2219 https://www.ncbi.nlm.nih.gov/clinvar/variation/2219/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transversion
CivicName: R167W (c.499C>G)
MultipleGeneVariants: N/A
PatientID: 6
KindredID: 2
Case: 15Y0M, Sex and Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: Recorded as a familial tumor; One other family member (Patient ID: 5) was a 29 year old patient with a bilateral pheochromocytoma. "Belonging to the same family", although the connection is unclear.
CasePresentingHPOs: HP:0002666 (Pheochromocytoma)
CaseHPOFreeText: Unilateral pheochromocytoma reported with an age at diagnosis of 15 years of age.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: RET, SDHB/SDHC/SDHD
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167W (c.499C>G)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 2219 https://www.ncbi.nlm.nih.gov/clinvar/variation/2219/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transversion
CivicName: R167W (c.499C>G)
MultipleGeneVariants: N/A
PatientID: 6 (Mother)
KindredID: 18
Case: F, 75Y0M, Ethnicity Unknown
DiseaseAssertion: Assumed VHL
FamilyInfo: 11 members of this family tested positive for the c.712C>T/c.499C>T germline variant of the VHL gene. 14 members of this family were assumed to carry this variant due to family history/personal medical history. Members of this family range from asymptomatic to multi-organ involvement (pheochromocytoma, pancreatic and renal cysts/tumors and hemangioblastomas). The family was previously reported in PMID 3942913.
CasePresentingHPOs: HP:0010797; HP:0009711 (Hemangioblastoma, Retinal capillary hemangioma)
CaseHPOFreeText: This patient presented with CNS hemangioblastoma (54Y) and retinal angioma (28Y).
CaseNotHPOs: HP:0005584; HP:0000077; HP:0001732; HP:0002666 (Renal cell carcinoma, Abnormality of the kidney, Abnormality of the pancreas, Pheochromocytoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 3942913 (some members of this family are previously reported (phenotypes only) but unable to match patients across papers with confidence)
SupplementalData: Supplementary Table 1.
Variant: N/A
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: Authors state that the c.712C>T germline familial variant of the VHL gene in this patient is “inferred from the family”. No genetic testing was done on this patient to confirm this. Being that this familial variant is out of bound with respect to the NM_000551.3 reference sequence, it was concluded that this variant is noted in the Latif et al. (1993) reference and was translated to c.499C>T (NM_000551.3).
MutationType: N/A
CivicName: N/A
MultipleGeneVariants: N/A
PatientID: 49 (Cousin)
KindredID: 18
Case: F, 62Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: 11 members of this family tested positive for the c.712C>T/c.499C>T germline variant of the VHL gene. 14 members of this family were assumed to carry this variant due to family history/personal medical history. Members of this family range from asymptomatic to multi-organ involvement (pheochromocytoma, pancreatic and renal cysts/tumors and hemangioblastomas). The family was previously reported in PMID 3942913.
CasePresentingHPOs: HP:0002666; HP:0009711; HP:0005584; HP:0010797 (Pheochromocytoma, Retinal capillary hemangioma, Renal cell carcinoma, Hemangioblastoma)
CaseHPOFreeText: This patient presented with retinal angioma (18Y) and pheochromocytoma (20Y). Age of diagnosis of CNS hemangioblastoma and renal cell carcinoma is unknown.
CaseNotHPOs: HP:0000077; HP:0001732 (Abnormality of the kidney, Abnormality of the pancreas)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 3942913 (some members of this family are previously reported (phenotypes only) but unable to match patients across papers with confidence)
SupplementalData: Supplementary Table 1.
Variant: p.R167W (c.499C>T)
LegacyVariant: c.712C>T
CaseProblemVariantFreeText: N/A
ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: N/A
gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1
VariantEvidence: A point mutation (c.712C>T) was found. Being that this variant is out of bound with respect to the NM_000551.3 reference sequence, it was concluded that this variant is noted in the Latif et al. (1993) reference and was translated to c.499C>T (NM_000551.3).
MutationType: missense_variant;transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
GroupID: 36
DiseaseAssertion: assumed VHL
GroupSize: 4
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: 4 of the 573 patients discussed in this paper were found to have the following mutation belonging to 3 families altogether.
GroupPresentingHPOs: HP:0006880; HP:0005584; HP:0009711 (cerebellar hemangioblastoma; renal cell carcinoma; retinal capillary hemangioma)
GroupHPOFreeText: all 4 patients had retinal angiomas diagnosed at a mean age of 30Y and cerebellar hemangioblastomas diagnosed with a mean age of 25Y, and 2 had RCC diagnosed at a mean age of 29Y
GroupNotHPOs: HP:0002666 (pheochromocytoma)
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Supplementary Table S1.
Variant: p.Y185* (c.555C>G)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 223233 https://www.ncbi.nlm.nih.gov/clinvar/variation/223233/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: stop_gained
CivicName: Y185* (c.555C>G)
MultipleGeneVariants: N/A
Of 246 patients affected with von Hippel-Lindau disease, 64 patients (26%) from 38 families had pheochromocytoma, including 33 newly diagnosed during screening studies and 31 treated before screening at NIH. Germline mutations in the VHL gene was determined from peripheral blood. Family 6101 was found with p.Tyr112His mutation in the VHL gene (legacy notation c.547T>C converted to NM_000551.3): one patient was in this family with pheochromocytoma, and retinal angioma. No other family information was provided.
GroupID: 6102
DiseaseAssertion: VHL
GroupSize: 3
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: Each group represents a family.
GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0002666; HP:0005584 (Retinal capillary hemangioma, Hemangioblastoma, Pheochromocytoma, Renal cell carcinoma)
GroupHPOFreeText: 1/3 members with pheochromocytoma, 3/3 members with CNS hemangioblastoma, 3/3 members with retinal angioma and 2/3 members with RCC. Diagnosed as a VHL Type 2B family.
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.G114R (c.340G>C)
LegacyVariant: c.553G>C
CaseProblemVariantFreeText: N/A
ClinVarID: 223193, https://www.ncbi.nlm.nih.gov/clinvar/variation/223193/
CAID: N/A
gnomAD: N/A
VariantEvidence: Variant reported as 553, G to C (Gly to Arg), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.340G>C, p.Gly114Arg (NM_000551.3).
MutationType: missense_variant;transversion
CivicName: G114R (c.340G>C)
MultipleGeneVariants: N/A
PatientID: V64
KindredID: V64
Case: Sex Unknown, Age Unknown, French
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Diagnosed with VHL Type 1.
CaseNotHPOs: HP:0002666 (Pheochromocytoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.E73* (c.217C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 223164, https://www.ncbi.nlm.nih.gov/clinvar/variation/223164/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition; stop_gained
CivicName: E73* (c.217C>T)
MultipleGeneVariants: N/A
PatientID: V265
KindredID: V265
Case: Sex Unknown, Age Unknown, French
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Diagnosed with VHL Type 1.
CaseNotHPOs: HP:0002666 (Pheochromocytoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.Y156C (c.467A>G)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 43600, https://www.ncbi.nlm.nih.gov/clinvar/variation/43600/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: Y156C (c.467A>G)
MultipleGeneVariants: N/A
III 10 26 6 PC (15 years) 1 retinal hb (16 years) T c.1-?_340 + ?del
PatientID: III
KindredID: 17
Case: Sex Unknown, 26Y0M, Danish
DiseaseAssertion: VHL
FamilyInfo: 2 other family members were found to have this VHL variant. Patient 17-I was asymptomatic. Patient 17-II presented with CNS hemangioblastoma (8Y).
CasePresentingHPOs: HP:0009711; HP:0001737 (Retinal capillary hemangioma, Pancreatic cysts)
CaseHPOFreeText: Diagnosed with VHL at age 10Y. Presented with 6 pancreatic cysts (15Y) and retinal hemangioblastoma (16Y). Age at the end of study: 26Y.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: Exon 1 Deletion (c.1-?_340+?del)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: exon_loss_variant
CivicName: Exon 1 Deletion
MultipleGeneVariants: N/A
7 I 4 40 3 retinal hb (8 + 16 years) M c. 499 C > T (p.Arg167Trp)
PatientID: I
KindredID: 7
Case: Sex Unknown, 40Y0M, Danish
DiseaseAssertion: VHL
FamilyInfo: One other family member presented with this variant and was asymptomatic.
CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)
CaseHPOFreeText: Diagnosed with VHL at age 4Y. presented with 3 retinal hemangioblastomas (8Y, 16Y). Age at the end of study: 40Y.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167W (c.499C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: N/A
gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
Genetic Aspects Here, the 3 described cases of ELST were associated with VHL disease. This autosomal-dominant inherited disease is known to be related to a germline mutation in the tumor suppressor gene VHL that has been mapped to chromosome 3p25. The VHL gene encodes a protein (pVHL) that plays an important role in tumor angiogenesis, accounting for the hypervascular pattern of the VHL-related tumors (4). Analysis of our series of cases underlines the interest of a VHL genetic testing, which allows 1) to identify VHL disease in the absence of family history in front of an isolated lesion; 2) in the case of a positive test, to complete imaging and ophthalmologic evaluation and to manage regular and prolonged follow-up to detect early asymptomatic tumors; 3) to propose a familial presymptomatic genetic testing in first relatives and a specific follow-up only for the positive mutation carriers; and 4) conversely, to reassure negative mutation carriers.
ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3
GenotypingMethod: N/A
SamplingMethod: N/A
This 51-year-old male first presented for workup of headaches and a family history of VHL. He was found to have three cerebellar hemangioblastomas (two left-sided cerebellar hemangioblastomas (LHB1, LHB2) and one right-sided cerebellar hemangioblastoma (RHB1), two supratentorial hemangioblastomas (right frontal, suprasellar), and multiple spinal HBs including a large left C7-T1 lesion (C7T1), a T5 (T5), right and left sided T11 lesions (RT11, LT11), L2-3 lesion (L23), and multiple small nerve root lesions of the cauda equine consistent with CNS HBs.The patient underwent urgent resection of the largest cerebellar lesion (LHB1) for obstructive hydrocephalus. Following, an oncologic workup was performed, which revealed bilateral RCC (grade III clear cell) requiring total right and partial left sided nephrectomies, pheochromocytoma requiring adrenalectomy, and a pancreatic neuroendocrine tumor. A clinical diagnosis of VHL was made, and genetic testing confirmed a genetic mutation of p.R167Q consistent with VHL.
PatientID: None
KindredID: 1
Case: M,53Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: The patient had a family history of VHL.
CasePresentingHPOs: HP:0006880, HP:0009713, HP:0010797, HP:0000238,HP:0005584, HP:0032241, HP:0030405, HP:0002666 (cerebellar hemangioblastoma, spinal hemangioblastoma, hemangioblastoma, Hydrocephalus, renal cell carcinoma, Cervical neoplasm, pancreatic endocrine tumour, pheochromocytoma)
CaseHPOFreeText: At age 51, he was found to have three cerebellar hemangioblastomas (two left-sided cerebellar hemangioblastomas (LHB1, LHB2) and one right-sided cerebellar hemangioblastoma (RHB1), two supratentorial hemangioblastomas (right frontal, suprasellar), and multiple spinal HBs including a large left C7-T1 lesion (C7T1), a T5 (T5), right and left sided T11 lesions (RT11, LT11), L2-3 lesion (L23), and multiple small nerve root lesions of the cauda equine consistent with CNS HBs. An oncologic workup revealed bilateral RCC (grade III clear cell), pheochromocytoma requiring adrenalectomy, and a pancreatic neuroendocrine tumor. The patient was subsequently started on Pazopanib. Twelve months following initiation of therapy, the C7T1 HB decreased in size from 14 mm to 12 mm as measured on post-contrast axial T1 MRI. Six months later, C7T1 was further decreased to 9.5 mm, resulting in an approximately 50% decreased volume from initiation of treatment and notably reducing the mass effect on the spinal cord. The L23 lesion also demonstrated reduced size during this time period, from 8 mm to 7.5 mm, while the remaining HBs and retroperitoneal lymph nodes remained stable or increased in size. Following 21 months of TKI therapy, the patient’s systemic disease was stable, and he was placed on a drug holiday. Six months following cessation of Pazopanib, many of the CNS HBs increased slightly, including the C7T1 lesion.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167Q (c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVar: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167Q (c.500G>A)
MultipleGeneVariants: N/A
GroupID: 49
DiseaseAssertion: VHL
GroupSize: 2
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: French
GroupAgeRange: N/A
GroupInfo: 2 members of this family presented with the c.496G>T germline variant of the VHL gene. Member 2046 had no renal involvement. Member 1258 presented with mild renal disease. Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.
GroupPresentingHPOs: HP:0009726 (Renal neoplasm)
GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]).
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 2 and 1 individuals respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family.
SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.
Variant: p.V166F (c.496G>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: V166F (c.496G>T)
MultipleGeneVariants: N/A
GroupID: 21
DiseaseAssertion: VHL
GroupSize: 3
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: French
GroupAgeRange: N/A
GroupInfo: 3 members of this family were found to harbor the c.340G>C germline variant of the VHL gene. Members 1070 and 744 had unknown renal involvement. Member 742 presented with moderate renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.
GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)
GroupHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral).
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531, where 2 individuals with this mutation are reported. It is unclear if one or both of these previously reported individuals correspond to members of the current family.
SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.
Variant: p.G114R (c.340G>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 223193, https://www.ncbi.nlm.nih.gov/clinvar/variation/223193/
CAID: N/A
gnomAD: N/A
VariantEvidence: Authors state that this mutation is predicted to disturb the splicing process.
MutationType: missense_variant;transversion
CivicName: G114R (c.340G>C)
MultipleGeneVariants: N/A
PatientID: 217
KindredID: 81
Case: F, 33Y0M, Chinese
DiseaseAssertion: VHL
FamilyInfo: The proband's brother had the same germline mutation, and presented with a CNS hemangioblastoma at 20, and a pheochromocytoma at 26. The proband's mother had a CNS hemangioblastoma at 35, however no genotyping information is available for her.
CasePresentingHPOs: HP:0010797; HP:0005584; HP:0001737; HP:0001732 (Hemangioblastoma, Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas)
CaseHPOFreeText: The patient presented with a CNS hemangioblastoma at age 24, renal cell carcinoma at 32, and multiple pancreatic cysts/tumors at 33.
CaseNotHPOs: HP:0009711; HP:0002666 (Retinal capillary hemangioma, Pheochromocytoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).
SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.
Variant: p.R167Q (c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167Q (c.500G>A)
MultipleGeneVariants: N/A
In four families, partial deletions of one or more exons were detected by Southern blot analysis
PatientID: 1
KindredID: A
Case: F, Age unknown, Turkish
DiseaseAssertion: VHL
FamilyInfo: 5 family members are grouped with this deletion (ages 16-37Y; mean 31Y). VHL was clinically diagnosed in, at minimum, the proband. See Fig. 2 for family pedigree. The proband’s last two brothers were not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.
CasePresentingHPOs: HP:0009711; HP:0010797; HP:0005584 (retinal capillary hemangioma; hemangioblastoma; renal cell carcinoma)
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0002666 (pheochromocytoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: Deletion of exons 1 and 2
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID:N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: HindIII and revealed an aberrant banding pattern in three affected family members (1, 2, and 9); Southern blot analysis after EcoR1 digestion, with the g7 probe and an internal control probe, demonstrated an extra band above the 20-kb normal fragment
MutationType: exon_loss_variant
CivicName: exon 1-2 deletion
MultipleGeneVariants: N/A
c.319C>G [p.Arg107Gly]
PatientID: 7
KindredID: 7
Case: 55Y0M, Sex unknown, Chinese
DiseaseAssertion: VHL
FamilyInfo: Positive -- Their father and brother both had the same germline mutation. Their father was screened after genetic testing and found to have a left RCC with lung metastasis at age 80, and their brother was asymptomatic.
CasePresentingHPOs: HP:0010797 (hemangioblastoma)
CaseHPOFreeText: CNS hemangioblastoma first presenting at 55Y
CaseNotHPOs: HP:0005584; HP:0002666; HP:0009715 (renal cell carcinoma, pheochromocytoma, Papillary cystadenoma of the epididymis)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R107G (c.319C>G)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 43599 https://www.ncbi.nlm.nih.gov/clinvar/variation/43599/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transversion
CivicName: R107G (c.319C>G)
MultipleGeneVariants: N/A
V#2exon 3c.485G > Ap.C162YCNS-HB
PatientID: 2
KindredID: 2
Case: Sex Unknown, Age Unknown, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0010797 (hemangioblastoma)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Yes
Variant: p.C162Y (c.485G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 223225, https://www.ncbi.nlm.nih.gov/clinvar/variation/223225/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: C162Y (c.485G>A)
MultipleGeneVariants: N/A
PatientID: None (Proband)
KindredID: 108
Case: M, 30Y0M, Spanish
DiseaseAssertion: VHL
FamilyInfo: Positive for familial antecedents. Family history of cerebellar hemangioblastoma.
CohortInfo: Probands belonging to 18 unrelated Spanish VHL families carrying germline VHL deletions.
CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: Exon 1-3 Deletion (c.1-?_642+?del)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: Germline IRAK2 (unclear if partial or complete) and ENST197804 gene deletions. Loss of exons 2-3 of HSPC300. Study provides evidence to show that loss of HSPC300 highly correlates with the absence of ccRCC in VHL patients.
MutationType: exon_loss_variant
CivicName: Exon 1-3 Deletion
MultipleGeneVariants: Germline, IRAK2, Deletion MultipleGeneVariants: Germline, ENST197804, Deletion MultipleGeneVariants: Germline, HSPC300, Exon 2-3 Deletion
PatientID: None
KindredID: 93
Case: M, 31Y0M, Spanish
DiseaseAssertion: VHL
FamilyInfo: Positive for familial antecedents. Family history of renal cysts and clear cell renal cell carcinoma.
CohortInfo: Probands belonging to 18 unrelated Spanish VHL families carrying germline VHL deletions.
CasePresentingHPOs: HP:0006880 (Cerebellar hemangioblastoma)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: Exon 3 Deletion (c.464-?_642+?del)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: Germline HSPC300 retention. Study provides evidence to show that loss of HSPC300 highly correlates with the absence of ccRCC in VHL patients.
MutationType: exon_loss_variant
CivicName: Exon 3 Deletion
MultipleGeneVariants: N/A
PatientID: 356
KindredID: 356
Case: Sex Unknown, 54Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: Family history is positive but no details provided.
CasePresentingHPOs: HP:0010797; HP:0001732 (Hemangioblastoma, Abnormality of the pancreas)
CaseHPOFreeText: CNS hemangioblastoma and pancreatic cyst or tumor.
CaseNotHPOs: HP:0006770; HP:0002666; HP:0000107; HP:0009711 (Clear cell renal cell carcinoma, Pheochromocytoma, Renal cyst, Retinal capillary hemangioma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished:N/A
SupplementalData: Table S1, S2 and S3
Variant: Complete Deletion
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: deletion
CivicName: Null (Complete deletion)
MultipleGeneVariants: N/A
PatientID: 173
KindredID: 173
Case: Sex Unknown, 49Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0000107; HP:0001732; HP:0006770 (Renal cyst, Abnormality of the pancreas, Clear cell renal cell carcinoma)
CaseHPOFreeText: Pancreatic cyst or tumor and clear cell renal cell carcinoma and renal cyst.
CaseNotHPOs: HP:0002666; HP:0009711; HP:0010797 (Pheochromocytoma, Retinal capillary hemangioma, Hemangioblastoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished:N/A
SupplementalData: Table S1, S2 and S3
Variant: Partial Deletion (3kb)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: deletion
CivicName: Partial deletion of 3kb
MultipleGeneVariants: N/A
The proband (Patient III‐1) was admitted into our ward in October 2015 with a complaint of an occipital headache for 1 month. He was conscious, and a physical examination did not reveal ataxia. Tests for cranial nerve function, limb sensation and motor function were unremarkable. Contrast‐enhanced brain magnetic resonance imaging (MRI) revealed a solid‐cystic mass in the vermis cerebelli and left cerebellar hemisphere (Figure (Figure2a),2a), indicating a radiological diagnosis of CH. Cerebellar tumor resection was performed through a sub‐occipital craniotomy under general anesthesia, and the tumor was completely removed. The tumor, which was 30 mm in diameter, was pink and soft and composed of dilated veins and dense blood capillaries. A postoperative pathological analysis of the tumor indicated a hemangioblastoma. The patient completed outpatient follow‐up in October 2018. The occipital headache had disappeared, brain MRI showed no recurrence, and abdominal computerized tomography (CT) revealed no neoplasms.
PatientID: III-3
KindredID: 1
Case: M, 25Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: Both of the patient’s uncles (Patient II-1 and II-4) were clinically diagnosed with VHL disease, and carried the mutation NM_000551.3:c.269A>T. Patient II-1 presented with RCCC at age 33 and cerebral hemangioblastoma at age 41. Patient II-4 presented with RCCC at age 53. The patient’s deceased father (Patient II‐3) and deceased aunt (Patient II‐5) were also clinically diagnosed with VHL disease, but the mutation was undetermined before death. His father died of advanced RCCC, and his aunt (Patient II‐5) died of a ruptured CH. The patient’s grandparents (Patient I-1 and I-2) were also deceased from other causes. The patient’s son (Patient IV‐1), wife (Patient III‐2), and mother (Patient II‐2) were healthy and did not carry the mutation. Their annual physical examination did not reveal a hemangioblastoma, kidney mass or abdominal cyst.
CasePresentingHPOs: HP:0006880 (Cerebellar hemangioblastoma)
CaseHPOFreeText: The 25Y male patient presented with occipital headache at 21Y. Upon initial examination, the patient was diagnosed with cerebellar hemangioblastoma and the tumour was resected. The patient completed outpatient follow‐up three years later. The occipital headache had disappeared, brain MRI showed no recurrence, and abdominal CT revealed no neoplasms.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.N90I (c.269A>T)
LegacyVariant: N/A
ClinVarID: 223172, https://www.ncbi.nlm.nih.gov/clinvar/variation/223172/
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: N90I(c.269A>T)
MultipleGeneVariants: N/A
In our study, group 5 represented the c.262T > C p.Trp88Arg mutation that included 21 patients from 2 families (Figure 4 and Table 3). Variability was observed in the mean age at onset for CHB and RCC, which were 41.1 ± 9.1 (range = 29–62) and 37.4 ± 12.9 (range = 23–65), respectively.
PatientID: 3
KindredID: 2 (group ID 5)
Case: M, 52Y0M, Chinese
DiseaseAssertion: assumed VHL
CohortInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 2 families with 21 members total were described, and phenotypic information was given for this group.
FamilyInfo: In family 2, 4 members were described in a 3 generation family. The patient’s father, sister, and niece were also present with the VHL mutation. See Fig 4 for family pedigree; Table 3 for details.
CasePresentingHPOs: HP:0010797; HP:0002666 (hemangioblastoma, pheochromocytoma)
CaseHPOFreeText: CNS hemangioblastoma and pheochromocytoma both presented at age of onset of 50Y
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.W88R (c.262T>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 496053 https://www.ncbi.nlm.nih.gov/clinvar/variation/496053/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: W88R (c.262T>C)
MultipleGeneVariants: N/A
In our study, group 5 represented the c.262T > C p.Trp88Arg mutation that included 21 patients from 2 families (Figure 4 and Table 3). Variability was observed in the mean age at onset for CHB and RCC, which were 41.1 ± 9.1 (range = 29–62) and 37.4 ± 12.9 (range = 23–65), respectively.
PatientID: 8
KindredID: 1 (group ID 5)
Case: M, 48Y0M, Chinese
DiseaseAssertion: assumed VHL
CohortInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 2 families with 21 members total were described, and phenotypic information was given for this group.
FamilyInfo: In family 1, 17 members were described. The first generation describes 5 members with the VHL mutation, each passing on the gene to further generations. Patient 8’s father and sister had this familial mutation. His one son had not been yet tested at the time of the study. See Fig 4 for family pedigree; Table 3 for details.
CasePresentingHPOs: HP:0010797 (hemangioblastoma)
CaseHPOFreeText: He had CNS hemangioblastomas at 40Y
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.W88R (c.262T>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 496053 https://www.ncbi.nlm.nih.gov/clinvar/variation/496053/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: W88R (c.262T>C)
MultipleGeneVariants: N/A
PatientID: None (Daughter)
KindredID: 1
Case: F, Age Unknown, Ethnicity Unknown
DiseaseAssertion: Asymptomatic
FamilyInfo: Maternal grandmother had cerebral vascular lesions. Mother presented with retinal capillary hemangioma, photophobia, macular thickening, vitreomacular traction, retinal exudate, retinal vascular proliferation, tractional retinal detachment and a 151 nucleotide deletion of the VHL gene.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: Partial Deletion
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: 151 nucleotide deletion in exon 1.
MutationType: deletion
CivicName: NULL (PARTIAL DELETION OF EXON 1)
MultipleGeneVariants: N/A
PatientID: ccRCC-159
KindredID: 159
Case: M, 59Y0M, Ethnicity Unknown
DiseaseAssertion: Clear Cell Renal Cell Carcinoma
FamilyInfo: N/A
CohortInfo: 240 ccRCC specimens.
CasePresentingHPOs: HP:0006770 (clear cell renal cell carcinoma)
CaseHPOFreeText:He was diagnosed with ccRCC at age 56.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Supplementary table 1.
Variant: c.464-1G>T
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 223221 https://www.ncbi.nlm.nih.gov/clinvar/variation/223221/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: splice_site_variant
CivicName: Splice Site (c.464-1G>T)
MultipleGeneVariants: N/A
MRI of the brain of the patient's brother (II-3) indicated a nodule in the left cerebellar tonsil with a size of ~9.0×10.5 mm, which indicated the presence of a hemangioblastoma, astrocytoma or ependymoma. However, the diagnosis could not be confirmed. Therefore, patient II-3 was regarded as a carrier of the mutant gene.
PatientID:II-3
KindredID: 2
Case: M, Sex Unknown, Chinese
DiseaseAssertion:Asymptomatic
FamilyInfo: The mother of the patient (I-2) was deceased, and the cause was unknown. The mother exhibited a brain tumor and coronary heart disease whilst alive. Multiple nodules were detected in the thyroid gland of the patient's eldest sister (II-1), but were not treated. Another sister (II-2) also had the mutation but was asymptomatic. See Figure 2 for pedigree.
CasePresentingHPOs: N/A
CaseHPOFreeText: MRI of the brain of the patient's brother (II-3) indicated a nodule in the left cerebellar tonsil with a size of ~9.0×10.5 mm, which indicated the presence of a hemangioblastoma, astrocytoma or ependymoma. However, the diagnosis could not be confirmed.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167W (c.499C>T)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 2218 https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: N/A
gnomAD: 0.000007954 https://gnomad.broadinstitute.org/variant/3-10191506-C-T
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
PatientID: 55
KindredID: 55
Case: F, 44Y0M, Korean
DiseaseAssertion: VHL
FamilyInfo: Family history positive for VHL. No further details provided.
CohortInfo: 26 Korean patients with more than one HAB in the CNS or eye, a single HAB in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts, pheochromocytoma and RCC) and positive family history plus any one of the above manifestations.
CasePresentingHPOs: HP:0010797 (Hemangioblastoma)
CaseHPOFreeText: CNS hemangioblastoma. Other phenotypes presented but not specified (one or more of: pancreatic cyst or tumor, renal or hepatic cyst). Diagnosed with VHL Type 1.
CaseNotHPOs: HP:0002666; HP:0009711; HP:0005584 (Pheochromocytoma, Retinal capillary hemangioma, Renal cell carcinoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 19270817
SupplementalData: N/A
Variant: Exon 1-3 Deletion (c.1-?_642+?del)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: exon_loss_variant
CivicName: Exon 1-3 Deletion
MultipleGeneVariants: N/A
PatientID: 43
KindredID: 43
Case: M, 30Y0M, Korean
DiseaseAssertion: VHL
FamilyInfo: No family history of VHL.
CohortInfo: 26 Korean patients with more than one HAB in the CNS or eye, a single HAB in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts, pheochromocytoma and RCC) and positive family history plus any one of the above manifestations.
CasePresentingHPOs: HP:0002666; HP:0009711 (Pheochromocytoma, Retinal capillary hemangioma)
CaseHPOFreeText: Multiple or bilateral pheochromocytoma. Other phenotypes presented but not specified (one or more of: pancreatic cyst or tumor, renal or hepatic cyst). Diagnosed with VHL Type 2A. Phenotypes revised from previous reports (see “PreviouslyPublished” section below for PMID).
CaseNotHPOs: HP:0010797; HP:0005584 (Hemangioblastoma, Renal cell carcinoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 19949673
SupplementalData: N/A
Variant: p.R167W (c.499C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: N/A
gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
PM 28 31 F ? ? ? - - - - VHL FLD – BRK1, FANCD2
PatientID: 28
KindredID: PM
Case: F, 31Y0M, Indian
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0010797; HP:0001737 (Hemangioblastoma, Pancreatic cysts)
CaseHPOFreeText: CNS hemangioblastoma and multi-cystic pancreatic lesions.
CaseNotHPOs: HP:0030393; HP:0009711; HP:0002666; HP:0005584 (Endolymphatic sac tumor, Retinal capillary hemangioma, Pheochromocytoma, Renal cell carcinoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: Complete Deletion
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: This variant is noted as a full-length deletion involving genes BRK1 and FANCD2.
MutationType: deletion
CivicName: Deletion
MultipleGeneVariants: N/A
All germline mutations in VHL,
PatientID: V-PH-05T
KindredID: 3
Case: F, 27Y0M, Ethnicity Unknown
DiseaseAssertion: assumed VHL
FamilyInfo: No familial cancers/syndromic illnesses
CasePresentingHPOs: HP:0002666; HP:0009711 (pheochromocytoma, retinal capillary hemangioma)
CaseHPOFreeText: diagnosed with recurrent phaeochromocytoma at age 12Y, surgery at 27Y. She also had a personal history of angioma of the right eye, laparotomy & numerous thyrocotomies, and a history of hypertension. Presence of elevated catecholamines, but no further details.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: RET, SDHA, SDHB, SDHC, TMEM127
PreviouslyPublished: 26796762
SupplementalData: Yes (see table S1 and S10)
Variant: p.T157I (c.470C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: Stated as ENSP00000256474.2:p.Thr157Ile
ClinVarID: 223223 https://www.ncbi.nlm.nih.gov/clinvar/variation/223223/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: T157I (c.470C>T)
MultipleGeneVariants: Germline, SDHA, c.113A>T (p.Asp38Val)
We identified deletions ranging from 0.5 kb to 250 kb affecting part of or the entire VHL and flanking genes in 54 families.
GroupID: 49
DiseaseAssertion: VHL
GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A
GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.
GroupPresentingHPOs: HP:0000107; HP:0010797; HP:0009713; HP:0001737 (Renal cyst, Hemangioblastoma, Spinal hemangioblastoma, Pancreatic cysts)
GroupHPOFreeText: # of affected individuals: Renal cyst (1), Hemangioblastoma/brain/cerebellum (4), Spinal hemangioblastoma (3), Pancreatic cysts (2)
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Supplemental Table 2, Table 1, Table 3
Variant: Exon 1-3 Deletion (c.1-?_642+?del)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: exon_loss_variant
CivicName: Exon 1-3 Deletion
MultipleGeneVariants: Germline, FANCD2, partial deletion
MultipleGeneVariants: Germline, IRAK2, deletion
221519N—N—NNYYNc.481C>T
PatientID: 22
KindredID: 15
Case: Sex Unknown, 19Y0M, Brazilian (Latino/Admixed American)
DiseaseAssertion: VHL
FamilyInfo: none
CasePresentingHPOs: HP:0010797; HP:0001737 (hemangioblastoma, pancreatic cyst)
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0002668, HP:0002666; HP:0009711; HP:0030405; HP:0005584; HP:0000107 (Paraganglioma, pheochromocytoma, retinal capillary hemangioma, pancreatic endocrine tumor, renal cell carcinoma, renal cyst)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R161* (c.481C>T)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 2217 https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: stop_gained
CivicName: R161* (c.481C>T)
MultipleGeneVariants: N/A
10412Y12Y13NNNNNc.500G>AExon 3p.Arg167GlnMissense
PatientID: 10
KindredID: 4
Case: M, 13Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: Four other family members were found to have the same mutation (Patients 6,7,8,9).
CasePresentingHPOs: HP:0002668, HP:0002666, HP:0030405 (Paraganglioma, pheochromocytoma, pancreatic endocrine tumor)
CaseHPOFreeText: The patient was diagnosed with a pancreatic endocrine tumor at age 13 it was found to be 0.7cm in size. He was diagnosed with pheochromocytoma and paraganglioma at age 12. He was found to have a right side pheochromocytoma measuring 5.5 cm and a left side pheochromocytoma measuring 1.5 cm. He was also found to have a paraganglioma measuring 2.2 cm.
CaseNotHPOs: HP:0009711, HP:0001737, HP:0000107, HP:0005584, HP:0010797 (retinal capillary hemangioma, pancreatic cysts, renal cyst, renal cell carcinoma, hemangioblastoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167Q (c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVar: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A
VariantEvidence:N/A
MutationType: missense_variant;transition
CivicName: R167Q (c.500 G >A)
MultipleGeneVariants: N/A
3Deletion
PatientID: unknown (sister)
KindredID: 13
Case: F, 30Y0M, Chinese
DiseaseAssertion: VHL
FamilyInfo: the patient’s brother was found with hemangioblastomas, RCC, and multiple pancreatic cysts or tumors at 23Y, and retinal angiomas at 24Y. Their mother was found at 43Y with CNS hemangioblastomas, however she died before diagnosis; no DNA sample was available.
CasePresentingHPOs: HP:0010797; HP:0005584; HP:0001737 (hemangioblastoma; renal cell carcinoma; pancreatic cysts)
CaseHPOFreeText: patient had hemangioblastomas, RCC, and multiple pancreatic cysts or tumors diagnosed at 30Y
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: exon 3 deletion
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: exon_loss_variant
CivicName: exon 3 deletion
MultipleGeneVariants: N/A
Nine patients were diagnosed with pheochromocytoma. Lumbal spinal hemangioblastoma and pancreatic neuroendocrine tumor without pheochromocytoma were detected in one patient. In patients with pheochromocytoma, additional tumors, such as retinal angioma, renal cell carcinoma, pancreatic serous cystadenoma, and pancreatic neuroendocrine tumors were detected. All patients were diagnosed as VHL syndrome type 2B.
PatientID: II-2
KindredID: 1
Case: F, 58Y0M, Turkish
DiseaseAssertion: VHL
FamilyInfo: 17 family members from three generations were examined with the c.445G>T mutation and diagnosed with VHL type 2B. 11 individuals had clinical manifestations and 6 were asymptomatic carriers. This patient’s 3 siblings had the mutation, 2 of her sons, and 3 grandchildren, and more. See Fig. 1 for detailed family pedigree.
CasePresentingHPOs: HP: 0006748; HP:0005584; HP:0001737; HP:0030405 (adrenal pheochromocytoma, renal cell carcinoma, pancreatic cysts, pancreatic endocrine tumor)
CaseHPOFreeText: Right adrenal nonfunctional pheochromocytoma; right renal cell carcinoma; Pancreatic serous cystadenoma (with a 7.3 cm tumor at 55Y), and this patient was reoperated 3 years later due to a pancreatic neuroendocrine tumor.
CaseNotHPOs: HP:0030393; HP:0009715 (endolymphatic sac tumor, papillary cystadenoma of the epididymis)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.A149S (c.445G>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 127829 https://www.ncbi.nlm.nih.gov/clinvar/variation/127829/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: A149S (c.445G>T)
MultipleGeneVariants: N/A
X214T one case (female)
PatientID: None
KindredID: 4
Case: F, 32Y0M, Ethnicity Unknown
DiseaseAssertion: Assumed VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0002666; HP:0001737 (Pheochromocytoma, pancreatic cyst)
CaseHPOFreeText: The patient presented with pheochromocytoma and pancreatic cysts. The age of diagnosis was not specified.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.*214Trpt*14(c.642A>G)
LegacyVariant: N/A
ClinVarID: 625269, http://www.ncbi.nlm.nih.gov/clinvar/variation/625269
gnomAD: N/A
VariantEvidence: N/A
MutationType: stop_loss
CivicName: *214Trpt*14(c.642A>G)
MultipleGeneVariants: N/A
Germline DNA was extracted from leukocytes according to standard protocols. Tumor samples were powdered in liquid nitrogen (30–50 mg for DNA extraction and 20–30 mg for RNA extraction). Tumor DNA was extracted using a QIAamp DNA mini kit or an AllPrep kit (Qiagen). RNAs were extracted using an RNeasy mini kit (Qiagen), analyzed by electrophoresis on a Bioanalyser 2100 (Agilent Technologies) and quantified using a NanoDrop ND-1000 spectrophotometer (Labtech). Stringent criteria for RNA quality were applied to rule out degradation, especially a 28S/18S ratio above 1.5. Genetic testing NF1 diagnosis was based on clinical criteria. Mutation analysis for RET, VHL, SDHB, SDHC and SDHD genes was performed by direct sequencing of germline DNA for each patient. When direct sequencing was negative, VHL, SDHB, SDHC and SDHD were also analyzed for the presence of large deletions using the MLPA (SALSA MLPA P016® version C1 for VHL and SALSA MLPA P226® version B1 for SDHx, MRC Holland, The Netherlands) method as described previously (44). Mutation analyses for SDHA and TMEM127 were performed retrospectively by direct sequencing and were limited to patients whose tumor presented a LOH assessed by BAC array CGH at the corresponding locus (5p15 for SDHA and 2q11 for TMEM127) (7,52). As mutations in the SDHAF2 gene were only described in patients with familial head and neck paragangliomas, we did not systematically analyze the SDHAF2 gene in this study. Mutation analysis for SDHAF1, IDH1 and IDH2 genes was performed by direct sequencing in candidate tumor samples.
ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3
GenotypingMethod: Direct sequencing, if negative, VHL, SDHB, SDHC and SDHD were also analyzed for the presence of large deletions using the MLPA (SALSA MLPA P016® version C1 for VHL and SALSA MLPA P226® version B1 for SDHx, MRC Holland, The Netherlands).
SamplingMethod: leukocytes and tissue resection
6 Deletion Deletion of exon 2 1 0
GroupID: 6
DiseaseAssertion: VHL
Group size: 1
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
Group Info: Retrospective analysis of a longitudinal cohort of 21 VHL germline mutation carriers and retinal haemangioblastomas. All patients were categorized in two genotypic categories: missense mutations and truncating mutations.
GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)
GroupHPOFreeText: This patient presented with retinal capillary hemangioma.
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Table S1
Variant: Exon 2 deletion
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: Chr3(GRCh37): g.10184170_10189331del c.341-4028_463+1011del5162
MutationType: deletion
CivicName: Exon 2 deletion
MultipleGeneVariants: N/A
MSon1c.208G > Ap.Glu70Lys–––––––14, 19
PatientID: Son
KindredID: 3
Case: M, Age Unknown, Korean
DiseaseAssertion: Asymptomatic
FamilyInfo: Mother presented with the same VHL mutation and bilateral retinal hemangioblastoma at 46Y. Since his aunt also had suffered from RHB, the mutation was considered to be passed down from his maternal grandparents.
CohortInfo: Thirteen unrelated patients with germline VHL mutations who were diagnosed with VHL disease were evaluated.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0002666; HP:0010797; HP:0005584; HP:0001732; HP:0000107; HP:0009711 (Pheochromocytoma, Hemangioblastoma, Renal cell carcinoma, Abnormality of the pancreas, Renal cyst, Retinal capillary hemangioma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.E70K (c.208G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 43598, https://www.ncbi.nlm.nih.gov/clinvar/variation/43598/
CAID: N/A
gnomAD: 0.000004365, https://gnomad.broadinstitute.org/variant/3-10183739-G-A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: E70K (c.208G>A)
MultipleGeneVariants: N/A
15PExon 3Missensec.500G>Ap. Arg167GlnPPGL, Metastatic PanNET
PatientID: 15
KindredID: 10
Case: Sex Unknown, Age Unknown, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0002668; HP:0030405 (paraganglioma, pancreatic endocrine tumor)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: MEN1/ RET
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167Q (c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/3-10191507-G-A
VariantEvidence: N/A
MutationType: missense_variant; transition
CivicName: R167Q (c.500G>A)
MultipleGeneVariants: N/A
ArticleReferenceSequence: Not specified- Assumption: Nucleotide change is not specified in the paper, only protein coding change is. cDNA variant was inferred based on protein coding change, and reported based on VHL reference sequence NM_000551.3
GenotypingMethod: Immunohistochemistry was performed as previously described on resected tumour using the P-16 polyclonal antibody to TFE (Santa Cruz Biotechnology, Santa Cruz, CA). Fresh tissue was sent to the Emory Cytogenetics Laboratory (Atlanta, GA) for karyotyping. Peripheral blood was sent to the DNA Diagnostic Laboratory of Johns Hopkins School of Medicine (Baltimore, MD), for sequence analysis of the VHL gene.
SamplingMethod: peripheral blood, tissue resection
c. 470C > T
PatientID: None
KindredID: 11
Case: age, sex, ethnicity unknown
DiseaseAssertion: Unknown
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Described as a positive control but not stated anything further
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: Likely previously published - not clear where the controls came from/ how they were used.
SupplementalData: N/A
Variant: p.T157I (c.470C>T)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 223223 https://www.ncbi.nlm.nih.gov/clinvar/variation/223223/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transition
CivicName: T157I (c.470C>T)
MultipleGeneVariants: N/A
GroupID: 11
DiseaseAssertion: VHL
GroupSize: 4
GroupNumberMales: N/A
GroupNumberFemales: N/A GroupEthnicity: Japanese GroupAgeRange: N/A
GroupInfo: The 4 patients are grouped based on both having the same mutation. They are unrelated to one another.
GroupPresentingHPOs: HP:0010797 (Hemangioblastoma)
GroupHPOFreeText: 4/4 patients in this group presented with CNS hemangioblastoma.
GroupNotHPOs: HP:0002666; HP:0009711; HP:0005584 (Pheochromocytoma, Retinal capillary hemangioma, Renal cell carcinoma)
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: 10761708
SupplementalData: N/A
Variant: p.C162Y (c.485G>A)
LegacyVariant: p.C233Y (c.698G>A)
CaseProblemVariantFreeText: N/A
ClinVarID: 43604, https://www.ncbi.nlm.nih.gov/clinvar/variation/43604/
CAID: N/A
gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/3-10191492-G-T?dataset=gnomad_r2_1
VariantEvidence: Nucleotide deletion (i.e. 698G>A) coincides with legacy variant nomenclature (i.e. AF010238.1) and was mapped to c.485G>A (NM_000551.3).
MutationType: missense_variant;transition
CivicName: C162Y (c.485G>A)
MultipleGeneVariants: N/A
Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors reported a nucleotide deletion (i.e. 697T>C) which coincides with legacy variant nomenclature (AF010238.1) and was mapped to c.484T>C (NM_000551.3). PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 4 had a C162R (c.484T>C) mutation. 2 members were affected: both had RCC, 1 had retinal angioma, and 1 had CNS Hb. We were not able to determine which member had more than one phenotype. Other demographics of the members were not described.
GroupID: 8
DiseaseAssertion: VHL
GroupSize: 5
GroupNumberMales: N/A
GroupNumberFemales: N/A GroupEthnicity: Japanese GroupAgeRange: N/A
GroupInfo: The 5 patients are grouped based on both having the same mutation. They are unrelated to one another.
GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)
GroupHPOFreeText: 5/5 patients in this group presented with RCC.
GroupNotHPOs: HP:0009711; HP:0010797; HP:0002666 (Retinal capillary hemangioma, Hemangioblastoma, Pheochromocytoma)
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: 10761708
SupplementalData: N/A
Variant: p.W88S (c.263G>C)
LegacyVariant: p.W159S (c.476G>C)
CaseProblemVariantFreeText: N/A
ClinVarID: 2220, https://www.ncbi.nlm.nih.gov/clinvar/variation/2220/
CAID: N/A
gnomAD: N/A
VariantEvidence: Nucleotide deletion (i.e. 476G>C) coincides with legacy variant nomenclature (i.e. AF010238.1) and was mapped to c.263G>C (NM_000551.3).
MutationType: missense_variant;transversion
CivicName: W88S (c.263G>C)
MultipleGeneVariants: N/A
three familial cases
PatientID: 7
KindredID: C
Case: M, Age Unknown, Japanese
DiseaseAssertion: Asymptomatic
FamilyInfo: This mutation was found in a family of 10 individuals; six were found to carry the mutation NM_000551.3:c.464-1G>T the patient carried, and three presented with symptoms. They were identified with hemangioblastomas of the central nervous system and retinal angiomas. The eldest patient also had renal cell carcinoma (patient C-1).
CasePresentingHPOs: N/A
CaseHPOFreeText: The paper states this case was not yet symptomatic, suggesting they may be too young to show symptoms yet
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: (c.464-1G>T)
LegacyVariant: (c.677-1G>T)
ClinVarID: 223221, http://www.ncbi.nlm.nih.gov/clinvar/variation/223221
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: splice_site_variant
CivicName: SpliceSite(c.464-1G>T)
MultipleGeneVariants: N/A
a blood DNA analysis was given and identified a well-known pathogenic VHL mutation c.239G>T; p.(Ser80Ile), which is associated with a severe phenotype
ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3
GenotypingMethod: Sanger sequencing of the VHL gene.
SamplingMethod: Blood.
A 39-year-old man with molecularly confirmed VHL disease presented with epistaxis in 2012. Molecular analysis had confirmed a germline VHL mutation in 2004. He had previously undergone excision of cerebellar haemangioblastoma in 2003. He had also undergone bilateral nephron sparing surgery for ccRCC (stage pT1a, Fuhrman grade up to 3) in 2005 and renal radiofrequency ablation in both 2008 and 2012. CT imaging demonstrated an ethmoid mass measuring 35 × 34 × 44 mm. The patient underwent endoscopic transsphenoidal resection of the lesion. Staging investigations were negative for metastatic disease.Two years later, in 2014, the patient developed symptoms of nasal obstruction. Sinonasal tumour recurrence was suspected. Imaging demonstrated limited progression in the nasal cavity. Excision biopsy was performed. Histology appeared consistent with the initial presenting sinonasal tumour. Excision appeared complete, with no evidence of residual tumour. Subsequently, symptoms recurred. Therapeutic excision was performed in 2015 and again in 2016. To date, the patient's VHL disease remains stable with no evidence of new lesions or metastatic disease.The patient remained under the management of specialist multidisciplinary (MDT) team which coordinated regular imaging surveillance and clinical review. The MDT recommended regular magnetic resonance imaging (MRI) surveillance with localised resection as applicable. More extensive surgery or adjuvant therapy was not felt to be indicated.
PatientID: None
KindredID: 1
Case: M, 39Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0006880, HP:0005584; HP:0030072 (Cerebellar hemangioblastoma, clear cell renal cell carcinoma, Paranasal sinus neoplasm)
CaseHPOFreeText: Previously undergone excision of cerebellar haemangioblastoma in 2003. He had also undergone bilateral nephron sparing surgery for ccRCC (stage pT1a, Fuhrman grade up to 3) in 2005 and renal radiofrequency ablation in both 2008 and 2012. CT imaging demonstrated an ethmoid mass measuring 35 × 34 × 44 mm. The patient underwent endoscopic transsphenoidal resection of the lesion in 2012. Two years later, in 2014, sinonasal tumour recurrence was suspected and imaging demonstrated limited progression in the nasal cavity. Excision biopsy was performed and appeared complete, with no evidence of residual tumour. Subsequently, symptoms recurred. Therapeutic excision was performed in 2015 and again in 2016. To date, the patient's VHL disease remains stable with no evidence of new lesions or metastatic disease.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: Exon 1 Deletion (c.1-?_340+?del)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: exon_loss_variant
CivicName: Exon 1 Deletion and c.341-50G>A
MultipleGeneVariants: Somatic, VHL, c.341-50G>A
Sanger sequencing and MLPA for mutation screeningWhole blood is taken from the patient's venous circulation and stored at 4 °C. Subsequently 200 µl of whole blood are used for genomic DNA extraction using the QIAsymphony CDN Kit, QIAsynphony SP (Qiagen, Hilden, Germany), which allows to obtain the eluted DNA ready for use. In short, the extraction procedure is divided into various steps starting with a lysis, where lysate and magnetic particles are transferred in the sample preparation cartridge, subsequently DNA binds to magnetic particles, and then two separation steps follow magnetic interspersed with a wash to arrive at the release of the eluate. The DNA quality and quantity were measured with a Qubit ds assay on Qubit 2.0 Fluorometer (Thermo Fisher Scientific, Monza, Italy). When we searched for germline mutations of the VHL gene, the coding regions and exon-intron boundaries were amplified by PCR: 100 ng of DNA was PCR-amplified using the forward and revers primers located at exon-intron boundaries, performed in standard reaction conditions with an initial denaturation at 95 °C for 5 min followed by 30 cycles each composed of 1 min at 95 °C, 30 s at 58 °C, 30 s at 72 °C, and a final extension of 7 min at 72 °C. Total PCR products were than purified using a PCR purification kit (Qiagen, Milan, Italy). To perform the cycle-sequencing reaction, 5 ng of DNA were then blended with each primer (0.8 µM) in a terminator ready reaction mix containing big dye terminators (Applied Biosystems, Thermo Fisher Scientific) and submitted to 1 minute at 96 °C and 25 cycles at 96 °C for 10 s, 50 °C for 5 s, 60 °C for 4 min. A second purification step was necessary for the big dye removal with DyeEx 2.0 Spin Kit (Qiagen). Five µl of marked and purified DNA were submitted to sequencing analysis with ABI PRISM 310 Genetic Analyser (Applied Biosystems). Subsequently we searched eventual genomic rearrangements using the MLPA test (multiplex ligation-dependent probe amplification/MRC Holland, SALSA Kit P016-C2 VHL version C2) approach. For analysis of MLPA data we used Coffalyser.Net software (MRC, Holland, Netherlands). Analysis of variant by querying different databases i.e. Clinvar-NCBI-NIH and Intervar (Clinical Interpretation of genetic variants by ACMG/AMP 2015 guideline) allowed us to classify the variant [14].
ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3
GenotypingMethod: PCR amplification of the coding regions and exon-intron boundaries followed by Sanger sequencing
SamplingMethod: Whole blood
PatientID: V-17
KindredID: 1
Case: M, Age Unknown, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: Family’s roots were traced to the German town of Leipzig in Saxony, from whence the original 11 siblings had immigrated to America around 1670. The following report is a 2011 updated pedigree on the previously reported Tisherman kindred. At the time of this study, 43/49 patients have undergone mutational analysis revealing the VHL familial mutation (Y112H) and 35/49 patients have clinical VHL manifestations. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. 6 members of the family (all deceased; 4 males, 2 females) had suspected VHL and 2 (males) of these were suspected to have had Pheo/PGL.
CasePresentingHPOs: HP:0002666; HP:0002668 (Pheochromocytoma, Paraganglioma)
CaseHPOFreeText: Phenotype noted as: Pheo/PGL (unclear which of the two or if both apply to this patient).
CaseNotHPOs: HP:0005584; HP:0009711 (Renal cell carcinoma, Retinal capillary hemangioma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 9201016; 8239848 (no genetic information; only phenotypes)
SupplementalData: N/A
Variant: p.Y112H (c.334T>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2222, https://www.ncbi.nlm.nih.gov/clinvar/variation/2222/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: Y112H (c.334T>C)
MultipleGeneVariants: N/A
Molecular analysisGenomic DNA was isolated from peripheral blood samples with ethylenediaminetetraacetic acid tetrasodium salt dihydrate (EDTA) of the patients by using EZ1 DNA Investigator Kit (Qiagen, Hilden, Germany). Primary quality control of the isolated DNA samples was performed using NanoDrop (Thermo Fisher Scientific, Waltham, MA), and samples having A260/280 values between 1.8 and 2.0 were included in the study.QIAseq Targeted DNA Panel (Qiagen, Hilden, Germany) was performed to analyze six genes (KIF1B, RET, SDHB, SDHD, TMEM127, and VHL). Libraries were prepared according to the manufacturer’s instructions. Quality control of the prepared libraries was applied with Qubit dsDNA BR Assay system (Invitrogen, Carlsbad, CA). Fastq files were performed on Illumina NextSeq550 (Illumina Inc., San Diego, CA, ABD). Libraries covering the target genes were prepared according to the QIAseq Targeted DNA Panel protocol (Qiagen, Hilden, Germany). Following the target enrichment process, libraries were sequenced on the Illumina NextSeq550 (Illumina Inc., San Diego, CA, ABD). QCI analysis (Qiagen, Hilden, Germany) was used for Quality control and ordering Variant Call Format file. Variant analysis was performed with Ingenuity software (Qiagen, Hilden, Germany).For verifying the variants and segregation analysis, primers were designed for all needed regions, and Sanger sequencing was performed using an ABI 3130 (Applied Biosystems, USA) capillary electrophoresis system.
ArticleReferenceSequence: NM_000551.4
GenotypingMethod: Next-generation sequencing method was explored; Sanger sequencing was used for verifying the variants.
SamplingMethod: peripheral blood
missense variants
PatientID: 31
KindredID: 31
Case: Sex Unknown, Age Unknown, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0010797; HP:0009711; HP:0100634 (hemangioblastoma, retinal capillary hemangioma, neuroendocrine neoplasm)
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0006770; HP:0030405; HP:0030421 (clear cell renal cell carcinoma, pancreatic neuroendocrine neoplasm, Epididymal neoplasm)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 29437867 (Family 1 - see here for more info)
SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.
Variant: p.S65A (c.193T>G)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 223160 https://www.ncbi.nlm.nih.gov/clinvar/variation/223160
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transversion
CivicName: S65A (c.193T>G)
MultipleGeneVariants: N/A
Materials and Methods Sample collection A cohort of 38 PPGL cases was used in this study. Fresh-frozen and/or FFPE tissue samples were collected from the Victorian Cancer Biobank (n = 9, four with matching fresh and FFPE tissue), Royal Brisbane Hospital (n = 3), Royal North Shore Hospital (n = 19), and The Tumor Bank at The Children's Hospital at Westmead (n = 7) (see Supplemental Table 1 for patient details). Nine tumors had previously been analyzed by exome-sequencing in a previous study (19). Samples and clinical data were collected under institutional human research ethics board approval according to the guidelines of the Australian National Health and Medical Research Council. Nucleic acid extraction FFPE Sections (5-μm each) were cut onto glass slides. Regions of surrounding normal tissue or tumor regions containing high levels of stroma or vasculature were marked for exclusion using hematoxylin and eosin staining. Tissue regions of interest were marked and macrodissected from the slide surface using a surgical blade. The tissue fragments were deparaffinized by incubation with 1 mL xylene. Tissue was recovered by high-speed centrifugation and removal of xylene supernatant, residual xylene was eliminated by incubation with 1 mL of absolute ethanol. For gene-expression analysis (Nanostring platform), RNA was extracted from deparaffinized tissue by proteinase K digestion and column chromatography using the RNeasy FFPE extraction kit (QIAGEN) in accordance with the manufacturer's protocol. For genotyping by MPS (MiSeq platform), DNA was extracted from deparaffinized tissue by proteinase K digestion and column chromatography using the DNeasy Blood and Tissue Kit (QIAGEN) in accordance with the manufacturer's protocol. Fresh frozen Between 10 and 30 mg of frozen tissue was placed in QIAzol (QIAGEN) reagent and mechanically disrupted using an Ultra-Turrex (IKA) dispersing instrument. The aqueous phase was separated by addition of chloroform followed by high-speed centrifugation. Total RNA was then purified by column chromatography using the miRNeasy RNA extraction kit (QIAGEN) in accordance with the manufacturer's protocol. Gene selection and pathway analysis A combined set of published microarray data was used to determine six robust disease subtypes as previously described (19). For each of the determined subtypes, all pairs one-vs-one and one-vs-rest differential gene expression analyses were performed using the empirical Bayesian procedure present within the limma package for R (45). The results were filtered for genes with log-fold change greater than 1 and ranked by P-value. For each class, the top 10 genes from each of the five one-vs-one comparisons were combined and then these nonredundant gene sets were intersected with the top 50 genes derived from a one-vs-rest comparison for the respective class. Seven genes were selected from the result of the intersection as representative for each class. In cases where the intersection did not yield at least seven genes, additional genes were selected from the relevant P-value-ranked one-vs-rest comparison. For biologically similar classes (VHL/SDHx and RTK1/3), high-ranking genes (by P-value) were selected from the relevant one-vs-one comparison to provide additional contrast. Nanostring Expression levels using the custom 52-gene panel were determined using the nCounter GX gene expression system (Nanostring Technologies) in accordance with the manufacturer's protocol. Briefly, RNA isolated from fresh-frozen tissue (100 ng) or FFPE tissue (300 ng) was combined with Reporter CodeSet, hybridization buffer, and Capture Probe Set then incubated at 65°C for 12 hours. Post-hybridization processing was performed using the Nanostring nCounter Prep Station and reporter probe counts were assayed on the Nanostring Digital Analyzer.To account for technical and sample variation experimental probes were normalized against positive control and housekeeping gene probes. The geometric mean of the positive control probes for each sample was determined to create a summarized positive control value (SPCV). A sample-scaling factor was determined for each sample by dividing the mean of the SPCVs of all samples by the SPCV for each sample. All experimental and housekeeping probes for each sample were multiplied by the respective sample-scaling factor. Using the positive control scaled data, this process was then repeated using the housekeeping gene controls in place of positive control probes. Support vector machine classifier Using the Affy package for R, expression values for the 46 classifier genes were extracted from the published microarray dataset and standardized to z scores (46). The standardized expression values were combined with the class labels determined through consensus clustering to form the training set for a support-vector machine (SVM). Normalized Nanostring probe counts were standardized to z scores for input as the testing set. Classification was performed using an SVM operated in linear classification mode (C-type) as implemented in the e1071 library for R. Multiclass classification was performed using k(k − 1)/2 (where k is the total number of classes) binary classifiers in a one-against-one approach with the appropriate class found by a voting scheme. Genotyping and targeted sequencing Massively parallel sequencing A custom gene panel (TruSeq Custom Amplicon Assay, Illumina), encompassing nine known PPGL susceptibility genes (MAX [NM_002382], SDHA [NM_004168], SDHB [NM_003000], SDHC [NM_003001], SDHD [NM_003002], SDHAF2 [NM_017841], RET [NM_020975], TMEM127 [NM_017849], and VHL [NM_000551]), was used for genotyping. DNA libraries were prepared (using 250 ng of DNA from each sample) and sequenced on a MiSeq platform (using 2 × 150-bp paired-end reads) according to the manufacturer's instructions (Illumina). FASTQ files (containing reads and their base call quality scores) were generated for each sample; and alignment of reads (banded Smith-Waterman algorithm) and variant calling using GATK (47) was processed by MiSeq Reporter (version 2.0, Illumina). Annotation of functional consequences to variant calls was performed using ANNOVAR (version 2013Jul) (48). Sanger sequencing Sanger sequencing confirmed all variants identified by MPS. In addition, assessment of HRAS exons 2 and 3 was performed in those samples classified as RTK1–3 by Nanostring, using the following primer sequences: exon 2-forward (5′-gtgggtttgcccttcagat-3′), exon 2-reverse (5′-agccctatcctggctgtgt-3′), exon 3-forward (5′-tgagaggtaccagggagagg-3′), exon 3-reverse (5′-acatgcgcagagaggacag-3′). IHC Sections (4-μm each) were cut for each tumor, dewaxed in xylene, and rehydrated through a graded ethanol series. Appropriate control tissues were used to verify the quality of each stain. Staining for chromogranin A was performed using a Roche Ventana Ultra immunostainer (Ventana Medical Systems). Antigen retrieval involved incubation with Ventana Ultra CC1 Conditioning Solution for 32 minutes. Chromogranin A primary antibody (Dako M0869 Clone DAK-A3) was diluted 1:400 with Ventana Antibody Dilution Buffer and incubated at 36°C for 20 minutes. Antibody detection was performed using Ventana OptiView DAB IHC Detection kit and slides were counterstained with hematoxylin. Immunohistochemistry for SDHB was performed using the Leica BondIII autostainer (Leica Biosystem). For SDHB a mouse monoclonal antibody (clone 21A11, ABCAM ab14714) was used at a dilution of 1 in 500. Antibody detection was performed using the biotin-free Bond Polymer Defined Detection System (DS9713 Vision Biosystems), according to the manufacturer's protocol.
ArticleReferenceSequence: NM_000551.3
GenotypingMethod: A custom gene panel (TruSeq Custom Amplicon Assay, Illumina), encompassing nine known PPGL susceptibility genes (MAX, SDHA, SDHB, SDHC, SDHD, SDHAF2, RET, TMEM127, and VHL, was used for genotyping. Sanger sequencing confirmed all variants identified by MPS.
SamplingMethod: Fresh-frozen and/or FFPE tissue samples
A 33-year-old Japanese woman had suffered back pain for seven years. She was referred to our institute because multiple solid tumors in the pancreas had gradually increased in size, which was pointed out at 27 years of age. She had a medical history of treatment for a variety of VHLD-associated tumors, including a pancreatic NET surgically resected at 14 years of age, hemangiomas of the fourth ventricle and cervical spinal cord operated at 19 years of age, and a renal cell carcinoma of the right kidney treated by nephrectomy at 30 years of age.
PatientID: None
KindredID: 1
Case: F, 33Y0M, Japanese
DiseaseAssertion: VHL
FamilyInfo: Her father and elder brother were also diagnosed with VHLD, with her father having a medical history of two surgical resections for pancreatic NET and associated metastatic recurrence in the liver.
CasePresentingHPOs: HP:0030405, HP:0009713, HP:0005584, HP:0010797 (Pancreatic endocrine tumor, Spinal hemangioblastoma, Renal cell carcinoma, hemangioblastoma)
CaseHPOFreeText: She first developed multiple solid tumors of the pancreas at age 27 and they continued to grow until she was referred to the institute at age 33. She had a pancreatic endocrine tumour at age 14. At age 19, she had hemangiomas of the fourth ventricle and cervical spinal cord and a renal cell carcinoma of the right kidney treated by nephrectomy at 30 years of age.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167Q (c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A
VariantEvidence: Immunohistochemical studies revealed that the tumor cells were positive for synaptophysin and chromogranin A.
MutationType: missense_variant;transition
CivicName: R167Q (c.500G>A)
MultipleGeneVariants: N/A
10PCCF25+VHL60/40Multiple−− VHL 3Germlinec.499C>Tp.Arg167TrpPathogenic
PatientID: 10
KindredID: 2
Case: F, 25Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: Patient has 2 siblings (patients 11 and 12) with the same mutation and pheochromocytoma.
CasePresentingHPOs: HP:0002666 (Pheochromocytoma)
CaseHPOFreeText: Bilateral pheochromocytomas (60mm and 40mm)
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: SDHB (NM_003000.2), SDHC (NM_003001.3), SDHD (NM_003002.2), SDHAF2 (NM_017841.2), RET (exons 10–11 and 13–16, NM_020975.4), TMEM127 (NM_017849.3), MAX (NM_002382.3).
PreviouslyPublished: N/A
SupplementalData: Table 2
Variant: p.R167W (c.499C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: N/A
gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T
VariantEvidence: SNParray analysis of tumour DNA did not show LOH at any locus.
MutationType: missense_variant;transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
PatientID: 28
KindredID: 18
Case: M, 11Y0M, Indian
DiseaseAssertion: VHL
FamilyInfo: Relevant family history but details are not made available.
CohortInfo: This retrospective study was conducted at Department of Endocrinology of a tertiary care health centre in Western India. Patients presented to our institute between 2008 and 2016 were included in the study. During the study period a total of 33 patients were suspected to have VHL syndrome based on clinical features among whom 31 patients were found to have mutation in VHL gene. All patients are of Asian Indian descent.
CasePresentingHPOs: HP:0002666; HP:0005584 (Pheochromocytoma, Retinal capillary hemangioma)
CaseHPOFreeText: Bilateral pheochromocytoma.
CaseNotHPOs: HP:0009711; HP:0010797; HP:0002668; HP:0030405; HP:0001737 (Renal cell carcinoma, Hemangioblastoma, Paraganglioma, Pancreatic endocrine tumor, Pancreatic cysts)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167W (c.499C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: N/A
gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
mutation
No mention of NM_000133.4:c.128G>A (p.Arg43Gln) in this paper.
mutation
No Case Level Evidence for NM_000133.4:c.128G>T (p.Arg43Leu)
.A37D
Only mention of NM_000133.4:c.110C>A (p.Ala37Asp) in this publication.
mutations
The only mention of NM_000133.4:c.135G>T (p.Lys45Asn) in this publication was in reference to other publications that have case level data on this specific variant.
, similarly to other HB-related changes(p.Cys28Arg/Gly/Tyr)
No case level data for NM_000133.4:c.82T>C (p.Cys28Arg) in this paper.
Table 1.
No evidence of NM_000133.4:c.84T>G (p.Cys28Trp) in this paper.
Molecular analysis of hemophilia B in Poland: 12 novel muta-tions of the factor IX gene®
NM_000133.4(F9):c.19A>T (p.Ile7Phe) is not reported in this paper.
Click here for additional data file.(2
NM_000133.4:c.128G>A (p.Arg43Gln) is mentioned in the paper, however, there is no case level data associated with the mentioned variant.
variants
No mention of NM_000133.4:c.138G>T (p.Arg46Ser) in this publication.
c.138GNT
A case of NM_000133.4:c.138G>T (p.Arg46Ser) is mentioned in this paper, but previously reported, and no case level evidence is given in this publication.
.A37D
Only mention of NM_000133.4:c.110C>A (p.Ala37Asp) in this publication.
MD-0448
Case#: MD-0448 proband, female, 18 years old (report), Spain.
CaseHPOs: HP:0007663, HP:0011003, HP:0000651, HP:0007641 (decreased visual acuity, high myopia, diplopia, dyschromatopsia)
CaseHPOsFreeText: Onset at 8 years. BCVA, 0.5 on the Snellen-equivalent decimal scale [Snellen equivalent, 20/40]). Rapid deterioration of vision. BCVA progressed to 0.3 (Snellen equivalent, 20/65) at age 9 years and to 0.2 (Snellen equivalent, 20/100) at 12 years but stable since then. Fundus exam showed a tigroid fundus, bull’s eye maculopathy, thin vessels, peripapillary atrophy, and optic pallor. Peripheral retina appeared normal. Photopic responses were undetectable by ERG, and scotopic responses were residual. Visual-evoked potential recorded pathologic responses, including low amplitude and enlarged latency (implicit time).
CasePreviousTesting: Screened for variants in the ABCA4 gene by ABCA4 genotyping microarray.
CaseMethod1: WES
GenotypingMethod: WES found no pathogenic variants in the genes known to be associated with the arCRD phenotype (ABCA4, ADAM9, C8orf37, CERKL, EYS, RPGRIP1, and TULP1), and no other plausible genetic variant.
Variant: c.651T>G (p.Cys217Trp), homozygous (NM_001017979.3(RAB28):c.574-1238T>G)
ClinVar: 225879
gnomAD: The highest population minor allele frequency in gnomAD is 0.00002904 in the Latino/Admixed American population; no homozygotes in any population.
VariantEvidence: Present only in isoform 2.
CaseAddInfo: The parents and unaffected sibling are all heterozygous for the variant.
Case#: Iannuzzi_1991_IV-1, M, age unknown, origin unknown
DiseaseAssertion: VWD type 2A
FamilyInfo: Affected mother, aunt, grandfather, and many other relatives. LOD score 3.61 reported (12 affected and genotype positive, 4 unaffected genotype positive. 4 affected also have HTT with vWD.
ParentalGenotype:
CasePresentingHPOs: As reported elsewhere (Hanna etal1984), the diagnosis of typeII AvWD was based on the following: bleedingtime, FVIII procoagulant activity, vFW:Ag, ristocetincofactoractivity, platelet aggregation studies, and vWF multimer analysis
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting:
GenotypingMethod: PCR-RFLP of exon 28 of VWF
Gene: VWF
Variant:
HGVS: NM_000552.5(VWF):c.4883T>C (p.Ile1628Thr)
ClinVarID: 284
CAID:
gnomAD: not reported
MultipleGeneVariants:
Case 13
Case: Case 13, ages 2-17, Croatian
DiseaseAssertion: VWF3
FamilyInfo:
ParentalGenotypes(s):
CasePresentingHPOs:
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText: bleeding score= 5, VWF:GPIbM (%)= 7.8, VWF:Ag (%)= 9.7, vWF:GPIbM/vWF:Ag ratio= 0.80, FVIII:C (%): 34, VWF: CBA (%)= 7.8
CasePreviousTesting:
Gene: VWF
Variant: c.4975C>T, p.Arg1659Ter
HGVS: NM_000552.5:c.4975C>T
ClinVar: 297
gnomAD: https://gnomad.broadinstitute.org/variant/12-6127609-G-A?dataset=gnomad_r2_1
Case#: Kumar_2016_ , M, 9 months (report)
DiseaseAssertion: VWD type 2B
FamilyInfo: no family history, de novo assertion but no testing to prove it.
ParentalGenotype: not reported
CasePresentingHPOs:
CaseHPOFreeText: low von Willebrand factor (vWF) antigen (32%) and ristocetin cofactor activity (<8%). loss of high-molecular-weight multimers, bruising, extensive bleeding
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: not reported
GenotypingMethod: exon 28 sequencing
Gene: VWF
Variant:
HGVS: NM_000552.5(VWF):c.3940G>C, p.V1314L
ClinVarID: 302
CAID:
gnomAD: not reported
MultipleGeneVariants:
V‐136
Case#: Elayaperumal_2018_ , M, 4 y.o. (onset), origin in India
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity, no family history
ParentalGenotype: not reported
CasePresentingHPOs:
CaseHPOFreeText: bleeding score of 14. VWF:Ag 0.83, FVlll:C of 1.9%.
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: not reported
GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.
Gene: VWF
Variant: homozygous c.757_770del
HGVS: NM_000552.3:c.757_770del (p.Thr253Cysfs*45)
ClinVarID: not found
CAID: CAR unable to parse. Error: unknown
gnomAD: not found
MultipleGeneVariants: not reported
2
Case#: 2, female, 25yo
DiseaseAssertion: VWD1
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0000421, HP:0000132, HP:0011891, HP:0004846, HP:0012147 (bruising susceptibility, epistaxis, Menorrhagia, Post-partum hemorrhage, Reduced quantity of VWF, Impaired ristocetin cofactor assay activity)
CaseHPOFreeText: Type A blood, VWF:Ag (0·55–2 iu/ml) pre = 0·48, VWF:RCo (0·55–2 iu/ml) pre = 0·53, FVIII:C (0·55–2 iu/ml) pre = 0·25, FVIII:C/VWF:Ag ratio = 0·52, VWF:FVIII binding (>20%) = N/A, VWF:FVIII binding/VWF:Ag (>0·7) = N/A, multiple surgical interventions with VWF concentrate with adequate haemostasis
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: N/A
CasePreviousTesting: RFLP; confirmatory sequencing
Gene: VWF
Variant 1: NM_000552.4(VWF):c.2561G>A (p.Arg854Gln)
ClinVar: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/
gnomAD: MAF = 0.005692 (European Non-Finnish); https://gnomad.broadinstitute.org/variant/12-6143978-C-T
Variant 2: N/A - stated to be a compound heterozygote for a 2N VWD and a presumed null mutation
Supplementary Data, Table 2
Variant noted to be present in 4 individuals
Variant: NM_000257.3(MYH7):c.2156G>A (p.Arg719Gln)
ClinVar: 14107, https://www.ncbi.nlm.nih.gov/clinvar/variation/14107/
gnomAD: n/a
Supplementary Data, Table 2
Case: Australian
DiseaseAssertion: HCM
CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm
CasePreviousTesting: electrocardiography, echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1)
CaseGenotypingMethod: DNA isolated from peripheral blood or buccal swabs, PCR, Sanger sequencing, segregation analysis, haplotype analysis of MYBPC3 and MYH7
Variant: NM_000257.3(MYH7):c.2087A>G (p.Asn696Ser)
ClinVar: 181173, https://www.ncbi.nlm.nih.gov/clinvar/variation/181173/
gnomAD: n/a
Supplementary Data, Table 2
Variant noted to be present in 4 individuals
Variant: NM_000257.3(MYH7):c.438G>T (p.Lys146Asn)
ClinVar: 43013, https://www.ncbi.nlm.nih.gov/clinvar/variation/43013/
gnomAD: n/a
Supplementary Data, Table 2
Case: Australian
DiseaseAssertion: HCM
CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm
CasePreviousTesting: electrocardiography, echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1)
CaseGenotypingMethod: DNA isolated from peripheral blood or buccal swabs, PCR, Sanger sequencing, segregation analysis, haplotype analysis of MYBPC3 and MYH7
Variant: NM_000257.3(MYH7):c.1370T>C (p.Ile457Thr)
ClinVar: 42840, https://www.ncbi.nlm.nih.gov/clinvar/variation/42840/
gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/14-23898201-A-G
Supplementary Data, Table 2
Variant noted to be present in 6 individuals
Variant: NM_000257.3(MYH7):c.1988G>A (p.Arg663His)
ClinVar: 42875, https://www.ncbi.nlm.nih.gov/clinvar/variation/42875/
gnomAD: 0.00001414, https://gnomad.broadinstitute.org/variant/14-23896042-C-T
Supplementary Data: S2 Table
Case 82: Spanish, 28yo, Female
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1
CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes
Variant: NM_000257.3(MYH7):c.745C>G (p.Arg249Gly)
ClinVar: 181322, https://www.ncbi.nlm.nih.gov/clinvar/variation/181322/
gnomAD: n/a
Supplementary Data: S2 Table
Case 139: Spanish, 44yo, Female
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1
CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes
Variant: NM_000257.3(MYH7):c.2156G>A (p.Arg719Gln)
ClinVar: 14107, https://www.ncbi.nlm.nih.gov/clinvar/variation/14107/
gnomAD: n/a
Supplementary Data: S2 Table
Case 159: Spanish, 65yo, Female
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1
CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes
Variant: NM_000257.3(MYH7):c.2167C>T (p.Arg723Cys)
ClinVar: 14095, https://www.ncbi.nlm.nih.gov/clinvar/variation/14095/
gnomAD: 0.00001194, https://gnomad.broadinstitute.org/variant/14-23895023-G-A
Supplementary Data: S2 Table
Case 157: Spanish, 71yo, Female
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1
CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes
Variant: NM_000257.3(MYH7):c.5342G>A (p.Arg1781His)
ClinVar: 43064, https://www.ncbi.nlm.nih.gov/clinvar/variation/43064/
gnomAD: 0.00001767, https://gnomad.broadinstitute.org/variant/14-23884421-C-T
Supplementary Data: S2 Table
Case 5: Spanish, 7yo, Male
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1
CaseGenotypingMethod: genomic DNA obtained from blood or saliva, PCR, Sanger Sequencing
Variant: NM_000257.3(MYH7):c.2146G>A (p.Gly716Arg)
ClinVar: 14105, https://www.ncbi.nlm.nih.gov/clinvar/variation/14105/
gnomAD: n/a
Supplementary Data: S2 Table
Case 232: Spanish, 32yo, Female
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1
CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes
Variant: NM_000257.3(MYH7):c.2155C>T (p.Arg719Trp)
ClinVar: 14104, https://www.ncbi.nlm.nih.gov/clinvar/variation/14104/
gnomAD: 0.00003185, https://gnomad.broadinstitute.org/variant/14-23895180-G-A
MultipleGeneVariants:
(1) TNNT2 Variant:
Variant: NM_000364.3(TNNT2):c.878G>A (p.Arg293His) listed in paper as c.857G>A (p.Arg286His)
ClinVar: 43677, https://www.ncbi.nlm.nih.gov/clinvar/variation/43677/
gnomAD: 0.00006936, https://gnomad.broadinstitute.org/variant/1-201328348-C-T
(2) ACTN2 Variant:
Variant: NM_001103.3(ACTN2):c.1930G>A (p.Ala644Thr)
ClinVar: 43920, https://www.ncbi.nlm.nih.gov/clinvar/variation/43920/
gnomAD: 0.0001629, https://gnomad.broadinstitute.org/variant/1-236917337-G-A
Supplementary Data: S2 Table
Case 6: Spanish, 54yo, Female
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1
CaseGenotypingMethod: genomic DNA obtained from blood or saliva, PCR, Sanger Sequencing
Variant: NM_000257.3(MYH7):c.2389G>A (p.Ala797Thr)
ClinVar: 42901, https://www.ncbi.nlm.nih.gov/clinvar/variation/42901/
gnomAD: 0.00002386, https://gnomad.broadinstitute.org/variant/14-23894525-C-T
Table 1 and 4
Case A37: Female, 40yo
DiseaseAssertion: DCM
FamilyInfo: positive family history
CaseHPOFreeText: interventricular septum thickness = 7.9mm, left ventricular end diastolic diameter = 61.3mm, left ventricular end systolic diameter = 42mm, left ventricular posterior wall thickness = 6.8mm, left atrium = 32.6mm, left ventricular ejection fraction = 48%
CasePreviousTesting: 12-lead ECG, echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing (LMNA, PRKAG2, SCN5A, MYH6)
CaseGenotypingMethod: genomic DNA collected from peripheral whole blood samples, PCR, high-throughput sequencing using PGM Sequencing 400 kit, variants verified via Sanger Sequencing
Variant: NM_000257.3(MYH7):c.77C>T (p.Ala26Val)
ClinVar: 37375, https://www.ncbi.nlm.nih.gov/clinvar/variation/37375/
gnomAD: 0.0005233, https://gnomad.broadinstitute.org/variant/14-23902865-G-A
2.01
Case 2.01: Family 2, Male, 35yo at follow-up
DiseaseAssertion: Hypertrophic cardiomyopathy
CaseHPOFreeText: maximum left ventricular wall thickness ≥ 13 mm, follow-up echo = 9mm, longitudinal stain follow-up = -17.5%
CaseNotHPOs: HP:0001712, HP:0011675, HP:0002094, HP:0100749 (left ventricular hypertrophy, arrhythmia, dyspnea, chest pain)
CasePreviousTesting: 2D and M mode echocardiographic measurements, electrocardiography, cardiac MRI, Holter monitoring, measurements of left ventricular wall thickness, cavity dimensions, structural abnormalities, systolic anterior movement of mitral leaflets, outflow gradients, and Doppler inflow parameters.
CaseGenotypingMethod: method not described
Variant: NM_000257.3(MYH7):c.1357C>T (p.Arg453Cys)
ClinVar: 14089, https://www.ncbi.nlm.nih.gov/clinvar/variation/14089/
gnomAD: n/a
HCM456
Case#: HCM456, male, 28 years, not a smoker
DiseaseAssertion: HCM
FamilyInfo: None
CasePresentingHPOs: 51mm LAD, 15mm LVST, 45mm LVEDD, 69% LVEF, 20mm Maxi LVWT, 90mmHg Maxi LVOTG, 124188740 raw RNA-seq reads, 116826920 HQ reads (94.07%), 96.65% mapping rate, 793088 total variant, 35368 exonic variant
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseGenotypingMethod: RNA-seq, read mapping, variant calling, identify functional variants, differential expression analysis, miRWalk miRNA target prediction, LncRNA annotation, Co-expression network analysis, PPI network analysis, gene over-representation analysis,
Variant: NM_000257.4(MYH7):c.1207C>T (p.Arg403Trp)
ClinVar: 14102 https://www.ncbi.nlm.nih.gov/clinvar/variation/14102/
CAID: N/A
gnomAD: absent
HCM491
Case#: HCM491, female, 30 years, not a smoker
DiseaseAssertion: HCM
FamilyInfo: None
CasePresentingHPOs: 44mm LAD, 23mm LVST, 32mm LVEDD, 75% LVEF, 28mm Maxi LVWT, 64mmHg Maxi LVOTG, 123213328 raw RNA-seq reads, 115698990 HQ reads (93.90%), 95.97% mapping rate, 756623 total variant, 34040 exonic variant
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseGenotypingMethod: RNA-seq, read mapping, variant calling, identify functional variants, differential expression analysis, miRWalk miRNA target prediction, LncRNA annotation, Co-expression network analysis, PPI network analysis, gene over-representation analysis,
Variant: NM_000257.4(MYH7):c.1987C>T (p.Arg663Cys)
ClinVar: 42874 https://www.ncbi.nlm.nih.gov/clinvar/variation/42874/
CAID: N/A
gnomAD: absent
HCM490
Case#: HCM490, female, 41 yrs, not a smoker
DiseaseAssertion: HCM
FamilyInfo: None
CasePresentingHPOs: 44mm LAD, 15mm LVST, 39mm LVEDD, 58% LVEF, 21mm Maxi LVWT, 63mmHg Maxi LVOTG, 109178274 raw RNA-seq reads, 102325212 HQ reads (93.72%), 96.79% mapping rate, 728218 total variant, 33873 exonic variant
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseGenotypingMethod: RNA-seq, read mapping, variant calling, identify functional variants, differential expression analysis, miRWalk miRNA target prediction, LncRNA annotation, Co-expression network analysis, PPI network analysis, gene over-representation analysis,
Variant: NM_000257.4(MYH7):c.4130C>T (p.Thr1377Met)
ClinVar: 42992 https://www.ncbi.nlm.nih.gov/clinvar/variation/42992/
CAID: N/A
gnomAD: 0.000008791 European (non-finnish) https://gnomad.broadinstitute.org/variant/14-23887458-G-A
HCM562
Case#: HCM562, female, 36 yrs, smoker
DiseaseAssertion: HCM
FamilyInfo: None
CasePresentingHPOs: 36mm LAD, 0mm LVST, 36mm LVEDD, 66% LVEF, 21mm Maxi LVWT, 70mmHg Maxi LVOTG, 119176332 raw RNA-seq reads, 113518840 HQ reads (95.25%), 96.63% mapping rate, 782848 total variant, 34382 exonic variant
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseGenotypingMethod: RNA-seq, read mapping, variant calling, identify functional variants, differential expression analysis, miRWalk miRNA target prediction, LncRNA annotation, Co-expression network analysis, PPI network analysis, gene over-representation analysis,
Variant: NM_000257.4(MYH7):c.427C>T (p.Arg143Trp)
ClinVar: 164401 https://www.ncbi.nlm.nih.gov/clinvar/variation/164401/
CAID: N/A
gnomAD: 0.0001087 East Asian https://gnomad.broadinstitute.org/variant/14-23901923-G-A
CasePT-92: United States
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)
NotHPOsFreeText: N/A
CaseAddInfo:
CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.
Variant: NM_000257.3:c.2782G>A (p.Asp928Asn)
ClinVar: 164313 https://www.ncbi.nlm.nih.gov/clinvar/variation/164313/
gnomAD: Not in gnomAD
CasePT-57: United States
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)
NotHPOsFreeText: N/A
CaseAddInfo:
CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.
Variant: NM_000257.3:c.1231G>A (p.Val411Ile)
ClinVar: 181339 https://www.ncbi.nlm.nih.gov/clinvar/variation/181339/
gnomAD: Latino 5.643e-5, Overall 2.121e-5 https://gnomad.broadinstitute.org/variant/14-23898464-C-T
CasePT-31: United States
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)
NotHPOsFreeText: N/A
CaseAddInfo: 1 other patient has the same genotype
CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.
Variant: NM_000257.3:c.2761G>A (p.Glu921Lys)
ClinVar: 181205 https://www.ncbi.nlm.nih.gov/clinvar/variation/181205/
gnomAD: Not in gnomAD
Supplementary Data Table S3
Case: 157
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant1: NM_000257.4(MYH7):c.1816G>A (p.Val606Met)
ClinVar: 14091 https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/
gnomAD: 0.00001548, https://gnomad.broadinstitute.org/variant/14-23896866-C-T
Variant2: NM_000257.4(MYH7):c.3853+7C>T
ClinVar: 42977 https://www.ncbi.nlm.nih.gov/clinvar/variation/42977/
gnomAD: 0.003956, https://gnomad.broadinstitute.org/variant/14-23888685-G-A
MultipleGeneVariants:
(1) SDHA Variant
Variant: NM_004168.4(SDHA):c.1886A>T (p.Tyr629Phe)
ClinVar: 224949 https://www.ncbi.nlm.nih.gov/clinvar/variation/224949/
gnomAD: 0.5249, https://gnomad.broadinstitute.org/variant/5-254599-A-T
Supplementary Data Table S3
Case: 296
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant: NM_000257.4(MYH7):c.2539_2541del (p.Lys847del)
ClinVar: 42913 https://www.ncbi.nlm.nih.gov/clinvar/variation/42913/
gnomAD: Not in gnomAD
MultipleGeneVariants:
(1) DOLK Variant
Current transcript of DOLK has a C at location 17 and a Pro rather than an Ala
Variant: c.17G>C (p.Gly6Ala)
ClinVar: N/A
gnomAD: N/A
(2) MYPN Variant
Variant: NM_032578.3(MYPN):c.2863C>T (p.Arg955Trp)
ClinVar: 192126 https://www.ncbi.nlm.nih.gov/clinvar/variation/192126/
gnomAD: 0.001449, https://gnomad.broadinstitute.org/variant/10-69948821-C-T
(3) PSEN1 Variant
Variant: NM_000021.4(PSEN1):c.953A>G (p.Glu318Gly)
ClinVar: 98094 https://www.ncbi.nlm.nih.gov/clinvar/variation/98094/
gnomAD: 0.03394, https://gnomad.broadinstitute.org/variant/14-73673178-A-G
Supplementary Data Table S3
Case: 320
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant: NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)
ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/
gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T
MultipleGeneVariants:
(1) NEXN Variant
Variant: NM_144573.3(NEXN):c.995A>C (p.Glu332Ala)
ClinVar: 47915 https://www.ncbi.nlm.nih.gov/clinvar/variation/47915/
gnomAD: 0.01350, https://gnomad.broadinstitute.org/variant/1-78395131-A-C
Supplementary Data Table S3
Case: 49
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant: NM_000257.3:c.4353+3G>T
CAID: CA041823, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA041823
gnomAD: 0.0002122, https://gnomad.broadinstitute.org/variant/14-23886709-C-A
MultipleGeneVariants:
(1) DMD Variant
Variant: NM_004006.2(DMD):c.2391T>G (p.Asn797Lys)
ClinVar: 94510, https://www.ncbi.nlm.nih.gov/clinvar/variation/94510/
gnomAD: 0.006548, https://gnomad.broadinstitute.org/variant/X-32509625-A-C
(2) JUP Variant
Variant: NM_002230.4(JUP):c.1942G>A (p.Val648Ile)
ClinVar: 45842, https://www.ncbi.nlm.nih.gov/clinvar/variation/45842/
gnomAD: 0.007385, https://gnomad.broadinstitute.org/variant/17-39913771-C-T
Supplementary Data Table S3
Case: 100
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant: NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)
ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/
gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T
MultipleGeneVariants:
(1) FBN1 Variant
Variant: NM_000138.4(FBN1):c.3077T>C (p.Phe1026Ser)
ClinVar: 199948 https://www.ncbi.nlm.nih.gov/clinvar/variation/199948/
gnomAD: 0.006608, https://gnomad.broadinstitute.org/variant/15-48782053-A-G
Supplementary Data Table S3
Case: 26
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant: NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)
ClinVar: 155814, https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/
gnomAD: 0.00006010, https://gnomad.broadinstitute.org/variant/14-23891476-C-T
MultipleGeneVariants:
(1) FBN1 Variant
Variant: NM_000138.4(FBN1):c.3077T>C (p.Phe1026Ser)
ClinVar: 199948, https://www.ncbi.nlm.nih.gov/clinvar/variation/199948/
gnomAD: 0.0006449, https://gnomad.broadinstitute.org/variant/15-48782053-A-G
(2) SDHA Variant
Variant: NM_004168.4(SDHA):c.1886A>T (p.Tyr629Phe)
ClinVar: 224949, https://www.ncbi.nlm.nih.gov/clinvar/variation/224949/
gnomAD: 0.1547, https://gnomad.broadinstitute.org/variant/5-254599-A-T
DiseaseAssertion: Hypertrophic Cardiomyopathy
VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.
VariantAddInfo: Seen in one HCM proband
Variant: NM_000257.4(MYH7):c.2221G>T (p.Gly741Trp)
ClinVarID: 177665 https://www.ncbi.nlm.nih.gov/clinvar/variation/177665/
gnomAD: Not in gnomAD
DiseaseAssertion: Hypertrophic Cardiomyopathy
VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.
VariantAddInfo: Seen in five HCM probands and one PanCM proband
Variant: NM_000257.4(MYH7):c.1750G>C (p.Gly584Arg)
ClinVarID: 14090 https://www.ncbi.nlm.nih.gov/clinvar/variation/14090/
gnomAD: 0.000008790, http://gnomad.broadinstitute.org/variant/14-23896932-C-G
DiseaseAssertion: None
VariantPreviousTesting: Some combination of ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, ABCC9, CTF1, DES, EMD, LDB3, LMNA, MYH6, RBM20, SGCD, TAZ, TCAP, TTN, VCL, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, TTR, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TMEM43, CASQ2 and RYR2 were tested via NGS.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.
Variant: NM_000257.4(MYH7):c.2890G>C (p.Val964Leu)
ClinVar: 42938 https://www.ncbi.nlm.nih.gov/clinvar/variation/42938/
gnomAD: 0.0008437, http://gnomad.broadinstitute.org/variant/14-23893148-C-G
DiseaseAssertion: Dilated Cardiomyopathy
VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, ABCC9, CTF1, DES, EMD, LDB3, LMNA, MYH6, RBM20, SGCD, TAZ, TCAP, TTN, and VCL were all tested via NGS.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 74 DCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.
VariantAddInfo: Seen in one DCM proband
Variant: NM_000257.4(MYH7):c.2711G>A (p.Arg904His)
ClinVarID: 42926 https://www.ncbi.nlm.nih.gov/clinvar/variation/42926/
gnomAD: Not in gnomAD
DiseaseAssertion: Hypertrophic Cardiomyopathy
VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.
VariantAddInfo: Seen in one HCM probands
Variant: NM_000257.4(MYH7):c.788T>C (p.Ile263Thr)
ClinVar: 43106 https://www.ncbi.nlm.nih.gov/clinvar/variation/43106/
gnomAD: 0.000008792, http://gnomad.broadinstitute.org/variant/14-23900635-A-G
DiseaseAssertion: Hypertrophic Cardiomyopathy
VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.
VariantAddInfo: Seen in one HCM proband
Variant: NM_000257.4(MYH7):c.2167C>T (p.Arg723Cys)
ClinVarID: 14095 https://www.ncbi.nlm.nih.gov/clinvar/variation/14095/
gnomAD: 0.00003266, http://gnomad.broadinstitute.org/variant/14-23895023-G-A
an affected Tunisian SCARMD patien
Case1: Male, Tunisia
CasePresentingHPOs: N/A
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: Proband is homozygous for this variant, Family is consanguinous, Immunostaining of the patient's muscle showed deficiency of all three sarcoglycan subunits, Variant was found in an affected sibling and in both other families in PMID:1303286
CasePreviousTesting: N/A
CaseGenotypingMethod: Rabbit and human y-sarcoglycan were identifed and genomic phages were found to hybridize to the same region implicated in linkage analysis for ARLGMD. RNA from a skeletal muscle biopsy was taken and the PCR products were directly sequenced revealing a homozygous deletion that was confirmed in the DNA via PCR amplification and sequencing.
PreviouslyPublished: PMID:1303286
Variant: SGCG, 1-BP DEL, 525T
ClinVar: 2004 https://www.ncbi.nlm.nih.gov/clinvar/variation/2004/
Also Reported As
Variant: NM_000231.2(SGCG):c.525del (p.Phe175fs)
ClinVar: 189243 https://www.ncbi.nlm.nih.gov/clinvar/variation/189243/
gnomAD: 0.00009671, https://gnomad.broadinstitute.org/variant/13-23869568-CT-C
KMP 18
Case KMP 18: Eastern Slovakia, Female, 71yo
DiseaseAssertion: hypertrophic cardiomyopathy
FamilyInfo: no family history
CaseHPOFreeText: left ventricular ejection fraction = 60%, New York Heart Association Classification I-II
CaseNotHPOFreeText: left ventricular outflow tract obstruction
CasePreviousTesting: 12-lead ECG, echocardiography, partial testing (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2)
CaseGenotypingMethod: genomic DNA collected from peripheral blood leukocytes, Sanger sequencing
Variant: NM_000257.3(MYH7):c.2845G>A (p.Glu949Lys)
ClinVar: 14093, https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/
gnomAD: n/a
KMP 1
Case KMP 1: Eastern Slovakia, Female, 39yo
DiseaseAssertion: hypertrophic cardiomyopathy
FamilyInfo: no family history
CaseHPOFreeText: left ventricular ejection fraction = 60%, New York Heart Association Classification I,
CaseNotHPOFreeText: left ventricular outflow tract obstruction
CasePreviousTesting: 12-lead ECG, echocardiography, partial testing (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2)
CaseGenotypingMethod: genomic DNA collected from peripheral blood leukocytes, Sanger sequencing
Variant: NM_000257.3(MYH7):c.2845G>A (p.Glu949Lys)
ClinVar: 14093, https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/
gnomAD: n/a
KMP7
Case KMP 7: Eastern Slovakia, Male, 36yo
DiseaseAssertion: hypertrophic cardiomyopathy
FamilyInfo: no family history
CaseHPOFreeText: left ventricular outflow tract obstruction, left ventricular ejection fraction = 60%
CasePreviousTesting: 12-lead ECG, echocardiography, partial testing (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2)
CaseGenotypingMethod: genomic DNA collected from peripheral blood leukocytes, Sanger sequencing
Variant: NM_000257.3(MYH7):c.2845G>A (p.Glu949Lys)
ClinVar: 14093, https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/
gnomAD: n/a
Supplementary Data table 1
Case:
DiseaseAssertion: hypertrophic cardiomyopathy
CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm
CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TNNC1, CSRP3, TCAP, ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TMEM43, TNNC1, TTN, TTR, VCL), electrocardiography
CaseGenotypingMethod: direct sequencing of all coding intron-exon boundaries of 12 genes (prior to 2012), next-generation sequencing (post 2012)
Variant: NM_000257.3(MYH7):c.1357C>T (p.Arg453Cys)
ClinVar: 14089, https://www.ncbi.nlm.nih.gov/clinvar/variation/14089/
gnomAD: n/a
Supplementary Data table 1
Case:
DiseaseAssertion: hypertrophic cardiomyopathy
CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm
CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TNNC1, CSRP3, TCAP, ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TMEM43, TNNC1, TTN, TTR, VCL), electrocardiography
CaseGenotypingMethod: direct sequencing of all coding intron-exon boundaries of 12 genes (prior to 2012), next-generation sequencing (post 2012)
Variant: NM_000257.3(MYH7):c.3169G>A (p.Gly1057Ser)
ClinVar: 42950, https://www.ncbi.nlm.nih.gov/clinvar/variation/42950/
gnomAD: 0.000007953, https://gnomad.broadinstitute.org/variant/14-23891465-C-T
Supplementary Data table 1
Case:
DiseaseAssertion: hypertrophic cardiomyopathy
CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm
CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TNNC1, CSRP3, TCAP, ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TMEM43, TNNC1, TTN, TTR, VCL), electrocardiography
CaseGenotypingMethod: direct sequencing of all coding intron-exon boundaries of 12 genes (prior to 2012), next-generation sequencing (post 2012)
Variant: NM_000257.3(MYH7):c.2146G>A (p.Gly716Arg)
ClinVarID: 14105, https://www.ncbi.nlm.nih.gov/clinvar/variation/14105/
gnomAD: n/a
Supplementary Data table 1
Case:
DiseaseAssertion: hypertrophic cardiomyopathy
CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm
CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TNNC1, CSRP3, TCAP, ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TMEM43, TNNC1, TTN, TTR, VCL), electrocardiography
CaseGenotypingMethod: direct sequencing of all coding intron-exon boundaries of 12 genes (prior to 2012), next-generation sequencing (post 2012)
Variant: NM_000257.3(MYH7):c.2167C>T (p.Arg723Cys)
ClinVar: 14095, https://www.ncbi.nlm.nih.gov/clinvar/variation/14095/
gnomAD: 0.00001194, https://gnomad.broadinstitute.org/variant/14-23895023-G-A
Supplementary Data table 1
Case:
DiseaseAssertion: hypertrophic cardiomyopathy
CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm
CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TNNC1, CSRP3, TCAP, ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TMEM43, TNNC1, TTN, TTR, VCL), electrocardiography
CaseGenotypingMethod: direct sequencing of all coding intron-exon boundaries of 12 genes (prior to 2012), next-generation sequencing (post 2012)
Variant: NM_000257.3(MYH7):c.728G>A (p.Arg243His)
ClinVar: 14126, https://www.ncbi.nlm.nih.gov/clinvar/variation/14126/
gnomAD: 0.000007953, https://gnomad.broadinstitute.org/variant/14-23900798-C-T
Supplementary Data table 1
Case:
DiseaseAssertion: hypertrophic cardiomyopathy
CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm
CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TNNC1, CSRP3, TCAP, ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TMEM43, TNNC1, TTN, TTR, VCL), electrocardiography
CaseGenotypingMethod: direct sequencing of all coding intron-exon boundaries of 12 genes (prior to 2012), next-generation sequencing (post 2012)
Variant: NM_000257.3(MYH7):c.2221G>C (p.Gly741Arg)
ClinVar: 14098, https://www.ncbi.nlm.nih.gov/clinvar/variation/14098/
gnomAD: 0.00003185, https://gnomad.broadinstitute.org/variant/14-23894969-C-T
Supplementary Data table 1
Case:
DiseaseAssertion: hypertrophic cardiomyopathy
CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm
CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TNNC1, CSRP3, TCAP, ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TMEM43, TNNC1, TTN, TTR, VCL), electrocardiography
CaseGenotypingMethod: direct sequencing of all coding intron-exon boundaries of 12 genes (prior to 2012), next-generation sequencing (post 2012)
Variant: NM_000257.3(MYH7):c.2788G>A (p.Glu930Lys)
ClinVar: 42933, https://www.ncbi.nlm.nih.gov/clinvar/variation/42933/
gnomAD: n/a
HCM125
CaseHCM125: 39 yrs report, Vietnam, Asian
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: Family history of sudden cardiac death
CasePresentingHPOs: HP:0002875, HP:0001712, HP:0031295, HP:0011103, HP:0001653, HP:0006698 (Exertional dyspnea, Left ventricular hypertrophy, Left atrial enlargement, Abnormality of the left ventricular outflow tract, Mitral regurgitation, Dilatation of the ventricular cavity)
HPOsFreeText: Maximal LV thickness 22 mm
CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy
CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.
Variant: NM_000257.4(MYH7):c.2207T>C (p.Ile736Thr)
ClinVar: 164342 https://www.ncbi.nlm.nih.gov/clinvar/variation/164342/
gnomAD: Not in gnomAD
Multiple Gene Variants
(1) MYH6 Variant
Variant: NM_002471.3(MYH6):c.5410C>A (p.Gln1804Lys)
ClinVar: 312843 https://www.ncbi.nlm.nih.gov/clinvar/variation/312843/
gnomAD: 0.002807, http://gnomad.broadinstitute.org/variant/14-23853806-G-T
HCM047
CaseHCM047: 59 yrs report, Vietnam, Asian
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: Family history of hypertrophic cardiomyopathy, Has a sister with MYBPC3 mutation with asymptomatic HCM (did not mention MYH7 mutation)
CasePresentingHPOs: HP:0002875, HP:0001712 (Exertional dyspnea, Left ventricular hypertrophy)
HPOsFreeText: Maximal LV thickness 20 mm
CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy
CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.
Variant: NM_000257.4(MYH7):c.1322C>T (p.Thr441Met)
ClinVar: 14122 https://www.ncbi.nlm.nih.gov/clinvar/variation/14122/
gnomAD: 0.002556, http://gnomad.broadinstitute.org/variant/14-23898249-G-A
Multiple Gene Variants
(1) MYBPC3 Variant
Variant: NM_000256.3(MYBPC3):c.2308G>A (p.Asp770Asn)
ClinVar: 36604 https://www.ncbi.nlm.nih.gov/clinvar/variation/36604/
gnomAD: 0.00008693, http://gnomad.broadinstitute.org/variant/11-47360071-C-T
HCM033
CaseHCM033: 30 yrs report, Vietnam, Asian
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: Family history of Sudden Cardiac Death and Hypertrophic Cardiomyopathy, Has a 7 year old son with the same variant but no symptoms
CasePresentingHPOs: HP:0001712, HP:0100749, HP:0002875, HP:0011103, HP:0031295 (Left ventricular hypertrophy, Chest pain, Exertional dyspnea, Abnormality of the left ventricular outflow tract, Left atrial enlargement)
HPOsFreeText: Maximal LV thickness 27 mm
CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy
CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.
Variant: NM_000257.4(MYH7):c.1063G>A (p.Ala355Thr)
ClinVar: 42820 https://www.ncbi.nlm.nih.gov/clinvar/variation/42820/
gnomAD: Not in gnomAD
WPW385
Case#: WPW385, 13 yrs
DiseaseAssertion: LYH, WPW, SVT
FamilyInfo: inherited
CasePresentingHPOs: Wolff-Parkinson-White syndrome, Supraventricular tachycardia, Left ventricular hypertrophy (HP:0001716, HP:0004755, HP:0001712)
CaseHPOFreeText: 0 ARIC, 0 THou, 2.03e-5 gnomAD, 3.3e-5 Exac, 7.7e-5 esp6500, 20.5 CADD_phred, 0 pLI,
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseGenotypingMethod: ECG, exome sequencing, gene analysis, burden analysis,
Variant: NM_000257.4(MYH7):c.2389G>A (p.Ala797Thr)
ClinVar: 42901 https://www.ncbi.nlm.nih.gov/clinvar/variation/42901/
CAID: N/A
gnomAD: 0.0001230 African/African American https://gnomad.broadinstitute.org/variant/14-23894525-C-T
Supplementary Material 4
Case M-16: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant: NM_000257.3(MYH7):c.2156G>A (p.Arg719Gln)
ClinVar: 14107, https://www.ncbi.nlm.nih.gov/clinvar/variation/14107/
gnomAD: n/a
Supplementary Material 4
Case M-29: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant: NM_000257.3(MYH7):c.2803G>A (p.Glu935Lys)
ClinVar: 14106, https://www.ncbi.nlm.nih.gov/clinvar/variation/14106/
gnomAD: n/a
Supplementary Material 4
Case M-20: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant: NM_000257.3(MYH7):c.2221G>T (p.Gly741Trp)
ClinVar: 177665, https://www.ncbi.nlm.nih.gov/clinvar/variation/177665/
gnomAD: n/a
Supplementary Material 4
Case M-19: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant: NM_000257.3(MYH7):c.2221G>T (p.Gly741Trp)
ClinVar: 177665, https://www.ncbi.nlm.nih.gov/clinvar/variation/177665/
gnomAD: n/a
CaseMYH7-35: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.1324C>T (p.Arg442Cys)
ClinVar: 177897 https://www.ncbi.nlm.nih.gov/clinvar/variation/177897/
gnomAD: East Asian 5.012e-5, Overall 2.121e-5 https://gnomad.broadinstitute.org/variant/14-23898247-G-A
CaseMYH7-32: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: 3 other probands share this genotype
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.1816G>A (p.Val606Met)
ClinVar: 14091 https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/
gnomAD: European (Non-Finnish) 1.548e-5, Overall 7.070e-6 https://gnomad.broadinstitute.org/variant/14-23896866-C-T
CaseMYH7-29: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.2093T>C (p.Val698Ala)
ClinVar: 42878 https://www.ncbi.nlm.nih.gov/clinvar/variation/42878/
gnomAD: Not in gnomAD
C
CaseC: 13 years diagnosis, Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: Three affected relatives (5 possibly affected), Mother died 44 y with heart failure, Brother SCD 16 y
CasePresentingHPOs: HP:0001639, HP:0005110 (Hypertrophic cardiomyopathy, Atrial fibrillation)
HPOsFreeText: Maximum left ventricular hypertrophy at 20 mm
CaseNotHPOs: N/A
NotHPOsFreeText: Sudden cardiac death event
CaseAddInfo: Heart transplant was required
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.2156G>A (p.Arg719Gln)
ClinVar: 14107 https://www.ncbi.nlm.nih.gov/clinvar/variation/14107/
gnomAD: Not in gnomAD
Multiple Gene Variants:
MYBPC3 Variant
Variant: NM_000256.3:c.818G>A (p.Arg273His)
ClinVar: 161312 https://www.ncbi.nlm.nih.gov/clinvar/variation/161312/
gnomAD: Latino 2.275e-4, Overall 9.182e-5 https://gnomad.broadinstitute.org/variant/11-47369411-C-T
CaseMYH7-41: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.611G>A (p.Arg204His)
ClinVar: 43095 https://www.ncbi.nlm.nih.gov/clinvar/variation/43095/
gnomAD: East Asian 5.012e-5, Overall 1.767e-5 https://gnomad.broadinstitute.org/variant/14-23900998-C-T
CaseMYH7-17: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.2609G>A (p.Arg870His)
ClinVar: 14120 https://www.ncbi.nlm.nih.gov/clinvar/variation/14120/
gnomAD: European (Non-Finnish) 1.549e-5, Overall 7.072e-6 https://gnomad.broadinstitute.org/variant/14-23894048-C-T
CaseMYH7-7: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.4124A>G (p.Tyr1375Cys)
ClinVar: 164293 https://www.ncbi.nlm.nih.gov/clinvar/variation/164293/
gnomAD: Not in gnomAD
CaseMYH7-14: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.2770G>A (p.Glu924Lys)
ClinVar: 14092 https://www.ncbi.nlm.nih.gov/clinvar/variation/14092/
gnomAD: Not in gnomAD
CaseMYH7-38: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.1051A>G (p.Lys351Glu)
ClinVar: 181335 https://www.ncbi.nlm.nih.gov/clinvar/variation/181335/
gnomAD: Not in gnomAD
Supplementary Data: Online Table 1a
Case:
CasePresentingHPOs: HP:0001631, HP:0001629 (atrial septal defect, ventricular septal defect)
CaseHPOFreeText: Trisomy 21
CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)
CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes
Variant: NM_000257.3(MYH7):c.976G>C (p.Ala326Pro)
ClinVar: 43117, https://www.ncbi.nlm.nih.gov/clinvar/variation/43117/
gnomAD: 0.00008846, https://gnomad.broadinstitute.org/variant/14-23899792-C-G
Supplementary Data: Online Table 3
Case:
CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)
CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes
Variant: NM_000257.3(MYH7):c.2945T>C (p.Met982Thr)
ClinVar: 42941, https://www.ncbi.nlm.nih.gov/clinvar/variation/42941/
gnomAD: 0.0008484, https://gnomad.broadinstitute.org/variant/14-23892910-A-G
Supplementary Data: Online Table 3
Case:
CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)
CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes
Variant: NM_000257.3(MYH7):c.4377G>T (p.Lys1459Asn)
ClinVar: 43012, https://www.ncbi.nlm.nih.gov/clinvar/variation/43012/
gnomAD: 0.0002937, https://gnomad.broadinstitute.org/variant/14-23886504-C-A
Supplementary Data: Online Table 2a
Case:
CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)
CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes
Variant: NM_000257.3(MYH7):c.689T>C (p.Phe230Ser)
ClinVar: 236543, https://www.ncbi.nlm.nih.gov/clinvar/variation/263543/
gnomAD: n/a
DCM-19
CaseDCM-19: Male, 5 year diagnosis, Caucasian, Germany
CasePresentingHPOs: HP:0001644, HP:0001635 (Dilated cardiomyopathy, Heart failure)
HPOsFreeText: LVEDD at 74 mm, LV-Ejection Fraction at 20%, Cardiac Index at 2.38
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: Proband treated with VAD and ICD, Sporadic family history of cardiac disease, Proband also has a variant in NEXN, Patient is heterozygous for MYH7 variant
CaseGenotypingMethod: Using a Cardiomyopathy gene panel of 46 genes, the proband's DNA was screened for variants. Afterwards, the variants were classified based on pathogenicity and modeled using predictive software.
Variant: NM_000257.3:c.1106G>A (p.Arg369Gln)
ClinVar: 42822 https://www.ncbi.nlm.nih.gov/clinvar/variation/42822/
gnomAD: Not in gnomAD
Multiple Gene Variants
NEXN Variant
Variant: NM_144573.3:c.1955A>G (p.Tyr652Cys)
ClinVar: 326 https://www.ncbi.nlm.nih.gov/clinvar/variation/326/
gnomAD: European (Non-Finnish) 1.407e-4, Overall 7.859e-5 https://gnomad.broadinstitute.org/variant/1-78408441-A-G
Jun-49
Case#: male, 19 yrs
DiseaseAssertion:
FamilyInfo: No apparent history or HCM or SCD
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: testing on rest of genes
CaseGenotypingMethod: MYH7 specific
Variant: NM_000257.4(MYH7):c.2803G>A (p.Glu935Lys)
ClinVar: 14106 https://www.ncbi.nlm.nih.gov/clinvar/variation/14106/
CAID: N/A
gnomAD: absent
CaseST4-89: Sweden
DiseaseAssertion: Idiopathic Dilated Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001644 (Dilated cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0002140, HP:0000822, HP:0001654, HP:0030955, HP:0000819, HP:0002666, HP:0000845, HP:0000820 (Ischemic stroke, Hypertension, Valvular heart disease, Alcoholism, Diabetes mellitus, Pheochromocytoma, Acromegaly, Thyroid disease)
NotHPOsFreeText: Patients were excluded for significant systemic infection, systemic diseases, previous cancer treatment including irradiation, and tachycardia-induced cardiomyopathy or other primary cardiomyopathy.
CaseAddInfo: N/A
CasePreviousTesting: See Supplemental Table 1
CaseGenotypingMethod: Genomic DNA was extracted from the patients. 41 exons of previously-reported genes that were reported in DCM patients were amplified and directly sequenced. Afterwards, the variants were aligned and sorted for pathogenicity.
Variant: NM_000257.3:c.3286G>T (p.Asp1096Tyr)
ClinVar: 42953 https://www.ncbi.nlm.nih.gov/clinvar/variation/42953/
gnomAD: European (Non-Finnish) 3.097e-4, Overall 1.414e-4 https://gnomad.broadinstitute.org/variant/14-23890217-C-A
Clinical case.
Case: Male, 4yo
CasePresentingHPOs: HP:0001324, HP:0001270, HP:0006830, HP:0003458, HP:0000467, HP:0003547, HP:0002650 (muscle weakness, delayed motor development, congenital hypotonia, Myopathic electromyogram, neck muscle weakness, shoulder girdle muscle weakness, scoliosis)
HPOsFreeText: sporadic congenital muscle weakness, decreased cardiac pump function, perinatal encephalopathy, rolled over at 7mo, left ventricular dilation, normal total creatine phosphokinase, unspecified muscle atrophy shown in histological exam, signs of dropped head syndrome, gluteal and quadricep muscle weakness, axial weakness distribution. At 4yo: weight = 14kg, height = 104cm, ejection fraction = 56%, able to walk if head is supported, preserved emotional and intellectual development
CaseNotHPOs: HP:0002098, HP:0002015, HP:0001635 (breathing difficulties, dysphagia, heart failure)
DiseaseEntity: DCM
InheritancePattern: not specified
FamilyInformation: family not consanguineous, no history of progressive muscular disorders or cardiomyopathy, pedigree in Fig. 1
CasePreviousTesting: WES
CaseGenotypingMethod: genomic DNA extracted from white blood cells of proband and parents, WES, confirmed findings in proband, parents and siblings via PCR-based bidirectional Sanger sequencing, abnormal MYH7 transcript confirmed in vivo by RT-PCR, paternity and maternity confirmed by multiplex STR typing of 15 loci
Variant: NM_000257.3:c.5655+5G>C, confirmed de novo by parental testing
No ClinVar or CAID
Case390: Male, Birth onset, Japan, Asian
DiseaseAssertion: Left ventricular noncompaction
CasePresentingHPOs: HP:0030682, HP:0025169 (Left ventricular noncompaction, Left ventricular systolic dysfunction)
HPOsFreeText: Left Ventricular Ejection Fraction at 43.5%, LVDD-Z score at 3.3833
CaseNotHPOs: HP:0011675, HP:0001635 (Arrhythmia, Heart failure)
NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes
CaseAddInfo: No family history
CasePreviousTesting: Genes tested include the 8 sarcomere genes as well as 65 more listed in Table S1.
CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each of the probands. Next Generation Sequencing of 73 genes related to cardiac function was performed, incorporating PCR amplification, and any variants found were subjected to filtering for frequency and pathogenicity. Any variants suggested to be pathogenic were confirmed by Sanger sequencing afterwards.
Variant: NM_000257.3:c.5740G>A (p.Glu1914Lys)
ClinVar: 43088 https://www.ncbi.nlm.nih.gov/clinvar/variation/43088/
gnomAD: Not in gnomAD
3
Case3: Male, 37 years report, Netherlands
CasePresentingHPOs: HP:0011663, HP:0011675, HP:0001279, HP:0005135, HP:0001707, HP:0004308 (Right ventricular cardiomyopathy, Arrhythmia, Syncope, Abnormal T-wave, Abnormality of the right ventricle, Ventricular arrhythmia)
HPOsFreeText: Positive EPS inducibility
CaseNotHPOs: HP:0001639, HP:0001635, HP:0001711 (Hypertrophic cardiomyopathy, Congestive heart failure, Abnormality of the left ventricle)
NotHPOsFreeText: ECG Depolarization abnormality, Cardiac transplant
CaseAddInfo:
CasePreviousTesting: No variants were in any of DSP, PKP2, DSG2, DSC2, and JUP. Patients were tested for variants in ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNC1, TNNI3, TNNT2, and TPM1.
CaseGenotypingMethod: 92 patients underwent panel sequencing of the specific genes listed above, and 45 were subject to Whole Exome Sequencing to locate variants. Afterwards, all variants were verified by PCR amplification and Sanger sequencing and filtered for pathogenicity.
Variant: NM_000257.3:c.5536C>T (p.Arg1846Cys)
ClinVar: 161321 https://www.ncbi.nlm.nih.gov/clinvar/variation/161321/
gnomAD: East Asian 5.441e-5, Overall 1.208e-5 https://gnomad.broadinstitute.org/variant/14-23884227-G-A
II-1
CaseBII-1: Female, 64 years diagnosis, Italy, Caucasian
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: See Figure 1
CasePresentingHPOs: HP:0005110, HP:0001639, HP:0004756, HP:0001712, HP:0005135, HP:0002094, HP:0001962, HP:0006682, HP:0001279, HP:0000821 (Atrial fibrillation, Hypertrophic cardiomyopathy, Ventricular tachycardia, Left ventricular hypertrophy, Abnormal T-wave, Dyspnea, Palpitations, Premature ventricular contractions, Syncope, Hypothyroidism)
HPOsFreeText: Widespread septal and apical late gadolinium enhancement, Max Left ventricular wall thickness of 20 mm, Left atrium diameter of 54 mm, Left ventricular ejection fraction of 56%, Apical aneurism, Latent tuberculosis
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: The ACM proband from Family B was genotyped for PKP2, DSP, DSC2, DSG2, JUP and CTNNA3; the HCM patient from Family B was genotyped for MYBPC3, MYH7, TNNI3 and TNNT2.
CaseGenotypingMethod: All patients in Family B were directly sequenced according to the found variants in CTNNA3 and MYH7. These variants were filtered for pathogenicity and prevalence and classified accordingly.
Variant: NM_000257.3:c.2631G>T (p.Met877Ile)
ClinVar: 417718 https://www.ncbi.nlm.nih.gov/clinvar/variation/417718/
gnomAD: Not in gnomAD
II-7
CaseBII-7: Male, 50 years diagnosis, Italy, Caucasian
DiseaseAssertion: Borderline Arrhythmogenic Cardiomyopathy
FamilyInfo: See Figure 1
CasePresentingHPOs: HP:0005133, HP:0006683 (Right ventricular dilatation, Abnormal ventricular filling)
HPOsFreeText: LVWT of 12 mm with an abnormal filling pattern, Mild right ventricular dilatation of 30 mm, Left atrium diameter at 45 mm, 62% ejection fraction
CaseNotHPOs: HP:0003115 (Abnormal ECG)
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: The ACM proband from Family B was genotyped for PKP2, DSP, DSC2, DSG2, JUP and CTNNA3; the HCM patient from Family B was genotyped for MYBPC3, MYH7, TNNI3 and TNNT2.
CaseGenotypingMethod: All patients in Family B were directly sequenced according to the found variants in CTNNA3 and MYH7. These variants were filtered for pathogenicity and prevalence and classified accordingly.
Variant: NM_000257.3:c.2631G>T (p.Met877Ile)
ClinVar: 417718 https://www.ncbi.nlm.nih.gov/clinvar/variation/417718/
gnomAD: Not in gnomAD
Multiple Gene Variants
CTNNA3 Variant:
Variant: NM_013266.3:c.2296_2298delTTG (p.Leu766del)
ClinVar: 100657 https://www.ncbi.nlm.nih.gov/clinvar/variation/100657/
gnomAD: Not in gnomAD
Table 5
Case EO21: Italian
DiseaseAssertion: HCM (early-onset)
FamilyInfo: positive family history
CasePreviousTesting: echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1), additional testing: (GLA, LAMP2, PRKAG2, TNNC1, MYH6, CSPR3, PLN, TCAP, CAV3), electrocardiography
CaseGenotypingMethod: Genomic DNA extracted from periphera whole blood, emulsion PCR, 17 HCM genes sequenced using Personal Genome Machine (PGM) IonTorrent sequencer, variants confirmed via Sanger sequencing
Variant: NM_000257.3(MYH7):c.2539_2541delAAG (p.Lys847del)
ClinVar: 42913, https://www.ncbi.nlm.nih.gov/clinvar/variation/42913/
gnomAD: n/a
Table 5
Case EO2: Italian
DiseaseAssertion: HCM (early-onset)
FamilyInfo: positive family history
CasePreviousTesting: echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1), additional testing: (GLA, LAMP2, PRKAG2, TNNC1, MYH6, CSPR3, PLN, TCAP, CAV3), electrocardiography
CaseGenotypingMethod: Genomic DNA extracted from periphera whole blood, emulsion PCR, 17 HCM genes sequenced using Personal Genome Machine (PGM) IonTorrent sequencer, variants confirmed via Sanger sequencing
Variant: NM_000257.3(MYH7):c.2156G>A (p.Arg719Gln)
ClinVar: 14107, https://www.ncbi.nlm.nih.gov/clinvar/variation/14107/
gnomAD: n/a
CaseMYH7-10: Japan, Asian
CasePresentingHPOs: HP:0001639, HP:0006685 (Hypertrophic cardiomyopathy, Endomyocardial fibrosis)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo:
CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each proband. They each had 95 genes associated with DCM, HCM, and other inherited cardiovascular diseases sequenced with a panel, including both the exons and spicing regions. Variants were then filtered for rarity and pathogenicity.
Variant: NM_000257.3:c.746G>A (p.Arg249Gln)
ClinVar: 14088 https://www.ncbi.nlm.nih.gov/clinvar/variation/14088/
gnomAD: Not in gnomAD
CaseMYH7-2: Japan, Asian
CasePresentingHPOs: HP:0001639, HP:0006685 (Hypertrophic cardiomyopathy, Endomyocardial fibrosis)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo:
CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each proband. They each had 95 genes associated with DCM, HCM, and other inherited cardiovascular diseases sequenced with a panel, including both the exons and spicing regions. Variants were then filtered for rarity and pathogenicity.
Variant: NM_000257.3:c.2546T>C (p.Met849Thr)
ClinVar: 42914 https://www.ncbi.nlm.nih.gov/clinvar/variation/42914/
gnomAD: Not in gnomAD
6
Case6: Female, 28 years diagnosis, China, Asian
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePresentingHPOs: HP:0001639, HP:0001667, HP:0006682 (Hypertrophic cardiomyopathy, Right ventricular hypertrophy, Premature ventricular contractions)
HPOsFreeText: 1 SCD risk factor, NYHA class is I, Right ventricular wall thickness 15 mm
CaseNotHPOs: HP:0002092, HP:0001642, HP:0030680 (Pulmonary arterial hypertension, Pulmonary stenosis, Congenital heart disease)
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CaseGenotypingMethod: Probands' genomic DNA was extracted from blood samples. WES was performed, with the resulting sequence data mapped to a reference genome and variants filtered for pathogenicity and predicted effects. All variants identified were confirmed via Sanger sequencing of the respective genes.
Variant: NM_000257.3:c.2167C>T (p.Arg723Cys)
ClinVar: 14095 https://www.ncbi.nlm.nih.gov/clinvar/variation/14095/
gnomAD: Not in gnomAD
MultipleGeneVariants:
MYBPC3 Variant:
Unknown Variant
Variant: MYBPC3-E334K
ClinVar: N/A
gnomAD: N/A
Case13: Male, 57 years diagnosis, China, Asian
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639, HP:0100749 (Hypertrophic cardiomyopathy, Chest pain)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: Probands were only genotyped for MYH7 and MYBPC3 in that order, stopping once a positive finding was detected.
CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood. Each gene's coding exons and flanking introns were subject to PCR amplification and sequencing. From there, any variants found were filtered for pathogenicity and low frequencies.
Variant: NM_000257.3:c.1987C>T (p.Arg663Cys)
ClinVar: 42874 https://www.ncbi.nlm.nih.gov/clinvar/variation/42874/
gnomAD: Not in gnomAD
proband
Case#: II:1, 36 yrs, male
DiseaseAssertion: HCM
FamilyInfo: Yes, mother (62 yr) also has HCM
CasePresentingHPOs: Syncope, mitral regurgiation (HP:0001279, HP:0001653)
CaseHPOFreeText: left ventricular wall thickness 19.2m, small width of flow beam 2.5mm
CaseNotHPOs: N/A
CaseNotHPOFreeText: left ventricle diameter, no abnormalities in motion of left ventricular wall (16 points), no echo or blood flow, normal morphology
CasePreviousTesting: N/A
CaseGenotypingMethod: cdfi, ultrasound, whole-exome sequencing, pedigree analyses, in silico anaylsis,
Variant: NM_000257.4(MYH7):c.2207T>C (p.Ile736Thr)
ClinVar: 164342 https://www.ncbi.nlm.nih.gov/clinvar/variation/164342/
CAID: N/A
gnomAD: absent
CaseCM1414: Male, 12 years diagnosis, Japan, Asian
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0001939 (Abnormality of metabolism/homeostasis)
NotHPOsFreeText: Neuromuscular disease, Malformation syndromes
CaseAddInfo: No family history of cardiomyopathy or sudden death, Proband found in Supplementary Table 2
CasePreviousTesting: 8 patients with HCM and one with RCM were analyzed by NGS for the eight sarcomere-encoding genes and MYP.
CaseGenotypingMethod: Probands were subject to PCR amplification and direct sequencing of 64 cardiomyopathy-associated genes, including the eight sarcomere-encoding genes. The variants were then filtered for rarity and tested for pathogenicity.
Variant: NM_000257.3:c.1358G>A (p.Arg453His)
ClinVar: 42838 https://www.ncbi.nlm.nih.gov/clinvar/variation/42838/
gnomAD: Not in gnomAD
CaseMYH7-1:
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText:
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePreviousTesting: All sarcomeric genes were tested in each proband. The probands were tested upon diagnosis, so no record of the method used is provided.
CaseGenotypingMethod: Each variant was classified for pathogenicity and rarity.
Variant: NM_000257.3:c.1013T>A (p.Val338Glu)
ClinVar: 492983 https://www.ncbi.nlm.nih.gov/clinvar/variation/492983/
gnomAD: Not in gnomAD
One patient, a 78-year-old man with a MYH7 mutation (c.5186_5188del) and normal cardiac assessment, had four family members (two sons, one daughter, and one nephew) who were diagnosed with the same MYH7 mutation and had ICDs implanted (two sons after cardiac arrest and the two remaining patients for primary prevention). Unfortunately, we have no available cardiac data for these patients.
Case: Male, 78yo
FamilyInfo: 2 sons, 1 daughter, and 1 nephew also diagnosed with same MYH7 variant and had ICDs implanted
CasePresentingHPOs: HP:0001324, HP:0003388 (muscle weakness, fatigability)
HPOsFreeText: congenital myopathy, normal cardiac assessment
CasePreviousTesting: ACTA1, BIN1, DNM2, MYH7, MTM1, NEB, RYR1, SCN4A, SEPN1, TPM2, TPM3
CaseGenotypingMethod: PCR amplification of exons of genes investigated and Sanger sequencing or NGS
Variant: NM_000257.4(MYH7):c.5177_5179AGA[3] (p.Lys1729del)
ClinVar: 42096, https://www.ncbi.nlm.nih.gov/clinvar/variation/42096/
gnomAD: absent
5
Case#: Patient 5, female
CasePresentingHPOs: HP:0003236, HP:0003325
CaseAddInfo: 64yo at onset, 67yo at diagnosis
VariantAllele1: NM_000152.4(GAA):c.-32-13T>G
ClinVar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G
Variant2Allele: NM_000152.4(GAA):c.525delT (p.Glu176Argfs)
ClinVar: 4033, https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/
gnomAD: 7.041e-05, http://exac.broadinstitute.org/variant/17-78078909-CT-C
PD04
Patient4: Female, southern China
CasePresentingHPOs:
HPOsFreeText: IOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)
ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/
gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A
Variant2: NM_000152.4(GAA):c.2185delC (p.Leu729Trpfs) **this is not the same protein transcript listed in paper (p.Thr729fsX8) but I could not find this in clinvar or allele registry)
ClinVar: 370552, https://www.ncbi.nlm.nih.gov/clinvar/variation/370552/https://www.ncbi.nlm.nih.gov/clinvar/variation/370552/
gnomAD: n/a
Detailed characteristics of these patients
Patient4: male, 18yo, juvenile onset
CasePresentingHPOs:
HPOsFreeText: LOPD, BMI = 19.7 / 20.7 / 22.2, WGMS = 0 / 0 / 0
CaseNotHPOs: HP:0002355
NotHPOsFreeText: did not require respiratory support
CaseAddInfo: homozygous
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.-32-13T>G
Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G
Case10: Male, 80 years report
HPOsFreeText: 7 years of ERT completed, 6 Minute Walking Test at 220 meters, Forced Vital Capacity at 44%
GenotypingMethod: GAA Gene Sequencing
Variant1: NM_000152.4:c.-32-13T>G
ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027
gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G
Variant2: NM_000152.4:c.1927G>A (p.Gly643Arg)
ClinVar: 4023 https://www.ncbi.nlm.nih.gov/clinvar/variation/4023/
gnomAD: European (Non-Finnish) 3.667e-5, Overall 2.479e-5 http://gnomad.broadinstitute.org/variant/17-78086713-G-A
CaseAddInfo: Late Onset Pompe Disease