Case#: 4, female, 5 days (onset), 3 y 11 mo (current), Chinese

CasePresentingHPOs: HP: 0008344. HP: 0012088, HP: 0001279, HP:0001254, HP: 0011968, HP: 0001942, HP: 001276, HP: 0002543, HP: 0011344 (elevated A keto acids in urine, abnormal urinary odor, unconsciousness, lethargy, feeding difficulties, metabolic acidosis, hypertonia, abnormal globus pallidus, severe global developmental delay)

HPOsFreeText: liver damage, blood ammomia: 129 uM, Hemoglobin: 59 g/L, Leucin: 1155.27 uM, Valine: 848.19 uM, Isoleucine: 374.34 uM, Alloisoleucine: 128.73 uM

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: unsure whether cis or trans

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_000709.3:c.178G>T (p.Glu60Ter), NM_000709.3c.491T>C (p.Leu164Pro),

ClinVar: n/a

CAID: CA406004676, CA406010453

gnomAD: not found

PMID 28321846

Gene: PAX6

Variant NM_001368894.2:c.-128-2del

Disease: Ocular dysgenesis

InheritancePattern: AD

Disease PAX6-related ocular dysgenesis MONDO:0800183

Proband 26.03 and apparently de novo

Case15 Male, Finland

CasePresentingHPOs HP:0003826, HP:0000202, HP:0001161, HP:0001829, HP:0001627, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260, HP:0007165

(Stillbirth, Oral cleft, Micrognathia, Hand polydactyly, Foot polydactyly, Congenital heart defect, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Type II lissencephaly, Periventricular neuronal heterotopia)

HPOsFreeText Crown-heel body length 45cm, body weight 2520g, brain weight 146g, polydactyly of toes with multiple extra toes, 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

CaseNotHPOs HP:0000157

(Tongue abnormality)

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 stillborn at 34+0wk gestational age

CasePMIDs n/a

Case10 Male, Finland

CasePresentingHPOs HP:0000347, HP:0001829, HP:0010066, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260, HP:0030449

(Micrognathia, Foot polydactyly, Duplicated hallux, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria,Type II lissencephaly, Therapeutic abortion)

HPOsFreeText Crown-heel body length 25cm, body weight 250g, Brain weight 35g, abnormal larynx/trachea, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, leptomeningeal heterotopia, neuroepithelia rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0000202, HP:0001161, HP:0001627, HP:0000157, HP:0002444, HP:0007165

(Oral cleft, Hand polydactyly, Congenital heart defect, Tongue abnormality, Hypothalamic hamartoma, Periventricular neuronal heterotopia)

NotHPOsFreeText Uterus duplex, hydranencephaly/anencephaly, hypothalamic hamartoma/bulging, true alobar or semilobar holoprosencephaly, widely separated hemispheres without midline structures; only meningeal remnants cross the midline showing classical open-book appearance of HLS

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 induced abortion at 19+5wk gestational age

CasePMIDs n/a

Case1 female, Finland

CasePresentingHPOs HP:0000202, HP:0000347, HP:0001341, HP:0000238, HP:0002126, HP:0007165, HP:0030449

(Oral Cleft, Micrognathia, Olfactory lobe agenesis, Hydrocephalus, Polymicrogyria, Periventricular neuronal heterotopia, Therapeutic abortion)

HPOsFreeText crown-heel length: 8cm, weight: 9g, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, neuroepithelial rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0001161, HP:0001829, HP:0001627, HP:0000157, HP:0002101, HP:0007370, HP:0010664, HP:0002444, HP:0007260

(Hand polydactyly, Foot polydactyly, Congenital heart defect, Tongue abnormality, Defective lung lobation, Callosal agenesis, Fused thalami, Hypothalamic hamartoma, Type II lissencephaly)

NotHPOsFreeText abnormal larynx/trachea, uterus duplex, hydranencephaly/anencephaly, hypothalamic bulging, leptomeningeal heterotopia, 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 induced abortion at 12+1wk gestational age

CasePMIDs n/a

Case1: Male, 42 yrs report

CasePresentingHPOs: HP:0002359, HP:0003324, HP:0002515, HP:0003391, HP:0003273, HP:0000098, HP:0002751, HP:0003691, HP:0000465, HP:0002792, HP:0001620, HP:0001284, HP:0003458, HP:0003557, HP:0003803, HP:0003715 (Frequent falls, Diffuse muscle weakness, Waddling gait, Gowers sign, Hip contracture, Tall stature, Kyphoscoliosis, Scapular winging, Webbed neck, Reduced vital capacity, High-pitched voice, Areflexia, EMG: myopathy, Increased fiber size variation, Type 1 muscle fiber predominance, Myofibrillar myopathy)

HPOsFreeText: Uncomplicated pregnancy and delivery, Difficulty sitting at 8 months, Inability to walk longer distances and must use a wheelchair outdoors at 15 yrs, Extreme gracility of the limb and trunk muscles, Partly irregular and abnormally coarse-meshed pattern of the intermyofibrillar network, Cap structures, Loss of thick filaments, Thickened fragments of Z-bands

CaseNotHPOs: HP:0008947, HP:0010628, HP:0040081, HP:0011675, HP:0003798 (Infantile muscular hypotonia, Facial muscle weakness, Abnormal levels of creatine kinase in blood, Arrhythmia, Nemaline bodies)

NotHPOsFreeText: N/A

CaseAddInfo: Healthy parents and two healthy brothers, Mutation is de novo

CasePreviousTesting: N/A

CaseGenotypingMethod: PCR and sequencing analysis were performed on genomic DNA, specifically the entire coding sequence of TPM2. A PCR fragment of exon 2 of TPM2 was sequenced in both parents and a sibling with negative results.

Variant: NM_003289.3:c.142_144delAAG (p.Lys49del)

ClinVar: 12466 https://www.ncbi.nlm.nih.gov/clinvar/variation/12466/

gnomAD: Not in gnomAD

Case#: Family MZ, Northern European

CasePresentingHPOs: HP:0001639 ( Hypertrophic cardiomyopathy)

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting:

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: PCR amplification followed by Cycle Sequencing

Variant: The nucleotide variant positions here refer to those described in the initial cloning of the gene in 1988 (PMID: 3336363), but nucleotide A595G here aligns to NM_001018005.2(TPM1):c.539A>G (p.Glu180Gly).

ClinVar: 12455

CAID: CA019017

gnomAD: 15-63060915-A-G not in gnomAD v4.0.0

VariantEvidence:

CaseAddInfo:

CasePMIDs: PMID:8327508

Case# B641-12, "European," Male

CasePresentingHPOs HP:0000787

CaseNotHPOs HP:0003159

CasePreviousTesting 30 genes previously linked to nephrolithiasis were screened by exon sequencing in these individuals, but no causative mutations were detected

CaseMethod1 NGS

CaseGenotypingMethod list of 18 hypothetical candidate genes and performed exon amplification with consecutive next-generation sequencing in a multicenter cohort of 348 individuals with nephrolithiasis or isolated nephrocalcinosis

Variant NM_134425.2(SLC26A1):c.166G>A (p.Ala56Thr)

ClinVar 242376

gnomAD 0.0005655

VariantEvidence Monitoring of intracellular pH in transfected HEK293 demonstrated that p.Ala56Thr had reduced anion exchange activity. (Figure 4)

CaseAddInfo homozygous, consanguineous parents

NonPatientCell myocardium of ventricle, UBERON:0001083

GeneAlteration The D307H mutation was introduced into the coding sequence of canine CASQ2 by site-directed mutagenesis. The canine CASQ2D307H coding sequence was inserted into an adenoviral vector to generate Ad-CASQ2D307H for subsequent gene transfer into adult rat ventricular myocytes.

FunctionalEvidence (fig. 2) More intracellular Ca2+ due to reduced ability of SR to store Ca2+

Add Fig. 4 Increased transients through Ca2+ sparks

FAVariants NM_001232.3(CASQ2):c.919G>C (p.Asp307His), 17610 link

NonPatientCell UBERON:0005424, "ARPE19 cells"

GOterm GO:0042802

GeneAlteration HD-Ad-F3iT494M was constructed by introducing the HA-tagged PRPF3 coding sequence carrying T493M mutation, under control of the Ubiquitin C promoter and followed by the bovine growth hormone poly(A) signal, into HD-Ad-F3i.

FunctionalEvidence T494M phosphorylates less readily than WT

FAVariants NM_004698.3(PRPF3):c.1481C>T (p.Thr494Met), 3352

First connection between pulmonary fibrosis and TERT?

genotypes in table S2

Case#: Shi_Proband III-1

Demographics: Male, 20y, China

CasePresentingHPOs: HP:0001300, HP:0001256, HP:0001337, HP:0002071, HP:0002063, HP:0007076, HP:0200085, HP:0001288,

Pregnancy, delivery nd perinatal period were normal. Learning difficulties were identified at 8y. Age at tremor onset was 12y. Hoehn and Yahr staging was 2.5. T1, T2, and Susceptibility Weighted Imaging (SWI)-weighted brain MRI showed low-signal intensities in the bilateral globus pallidus, whereas CT scan showed high-density calcification in the same area. Treatment with Levodopa resulted in slight relief from tremor. Unified Parkinson’s Disease Rating Scale (UPDRS) - 32; Montreal Cognitive Assessment (MoCA) - 15; Mini-Mental State Examination (MMSE) - 20

CaseNotHPOs:

CasePreviousTesting:

CaseMethod1: WES

CaseMethod2: Sanger

CaseGenotypingMethod: WES was performed, followed by sequencing of the entire RAB39B coding region and exon-intron boundaries.

Variant: NM_171998.4:c.536dup (Ile180Aspfs*48)

ClinVar: CA1139768479

CAID:

gnomAD: NR

VariantEvidence: The proband was hemizygous for the null variant, Ile180AspfsTer48. The variant is predicted to cause extension of the protein with loss of the natural stop codon. In the absence of functional evidence supporting loss of function due to the variant, reduced points are awarded.

CaseAddInfo: Proband's parents were noted to be nonconsanguineous

CasePMIDs:

Case: Campeau Patient 1/Whyte Proband, female, 3 yo at report, American

CasePresentingHPOs: HP:0004322, HP:0000256, HP:0000592, HP:0410018, HP:0001581, HP:0003565, HP:0002007, HP:0002694, HP:0000885, HP:0000926, HP:0005019, HP:0100039, HP:0002757, HP:0000270, HP:0001518, HP:0002027, HP:0002829, HP:0001387, HP:0001742, HP:0030350, HP:0000348, HP:0005280, HP:0002714, HP:0002705, HP:0000369, HP:0011800, HP:0002857, HP:0012770, HP:0003300, HP:0005789, HP:0011002

CasePresentingHPOsFreeText: Broad ribs with sclerosis. Pelvis, peripheral sclerosis. Diaphyseal relative hypodensity. Painless, episodic erythematous papules usually on lower abdomen, legs, or arms. Serum BAP, osteocalcin, and TRACP-5b levels all were consistently low. Maxillary and ethmoid sinuses were opaque at ages 22 and 33 months, and the mastoid air cells were small. Increased amounts of cartilage, decreased hematopoietic marrow, and an absence of identifiable osteoclasts.

CaseNOTHPOs: HP:0100543, HP:0000504, HP:0000364, HP:0001595, HP:0000164, HP:0011329, HP:0000238, HP:0430048

CaseNOTHPOSFreeText: Abnormal serum glucose level. Bony tenderness.

CasePreviousTesting: Candidate gene sequencing. No notable variants int CLCN7, TCIRG1, or OSTM1. PCR and sequencing in both directions of all coding exons and adjacent mRNA splice sites of TNFRSF11A, TNFRSF11B, CSF1, CSF1R, and ANKH revealed no mutations. (c.107C > G, p.Pro36Arg) was found in TNFSF11, but not thought to be causal. Microarray-based genomic copy-number analysis of the patient and parents also was unrevealing.

CaseGenotypingMethod: WES

Variant: p.Ser203Pro (c.607T>C) and p.Arg386Gln (c.1157G>A)

ClinVarID: or CAID: CA130662; CA130660

gnomAD: The missense variant Ser203Pro is present in gnomAD v4.0.0 with a MAF=0.00002989 (1/33454 alleles) in the African/African American population and 0 homozygotes.

The missense variant Arg386Gln is present in gnomAD v4.0.0 with a MAF=0.00003999 (3/75018 alleles) in the African/African American population and 0 homozygotes.

AddCaseInfo: Heteroygous, non-consanguineous parents. Father is of Turkish ancestry. The mother's family emigrated to Turkey from Greece 70 years ago. Proband has two healthy brothers. No family history of skeletal disease

PreviouslyPublished: Whyte et al. PMID: 20499338

VariantEvidence: n/a

This variant has already been scored in homozygosity. Will consider scoring if necessary, but leaving out of curation for now.

W31R variant in homozygosity

Case#: Family IV-III:1, 26 year old, male

CaseHPOs: HP:0003563 (decreased LDL cholesterol)

CaseNotHPOs: HP:0000819 (Diabetes)

CasePreviousTesting: TC 102 mg/dl, LDL-C 36 mg/dl, HDL-C 57 mg/dl, TG 46 mg/dl (see additional values in Table 1)

Variant: NM_000384.2:c.11153C>G (p.Ser3718Ter), heterozygous

CAID: CA345983128

gnomAD: Absent

Variant evidence: APOB- p.Ser3718* mutations lead to the formation of expected truncated ApoB forms (ApoB-81) of 418 kDa (Fig. 1C, right panel) that can be secreted by the liver and lipidated.

CaseAddInfo: Son of Family IV-II:1

Case: Family III-II:2, female, 24 years

CaseHPOs: HP:0003563, (decreased LDL cholesterol)

CaseNotHPOs: HP:0000819 (Diabetes)

CasePreviousTesting: TC 143 mg/dl, LDL-C 28 mg/dl, HDL-C 110 mg/dl, TG 26 mg/dl (see additional values in Table 1). ApoB100 40 mg/dl (normal range 49-88) (Supplemental data). Normal ranges- total cholesterol (TC) 92-234 mg/dl, LDL-cholesterol (LDL-C) 136-174 mg/dl, HDL-cholesterol (HDL-C) 60-95 mg/dl), triglyceride (TG) 35-132 mg/dl.

Variant: NM_000384.2:c.8799C>A (p.Cys2933*), heterozygous

CAID: CA345993342

gnomAD: Absent

Variant evidence: APOB-p.Cys2933* leads to the formation of expected truncated ApoB form (ApoB-64) of 330 kDa (Fig. 1C, right panel) that can be secreted by the liver and lipidated.

Case# Wang II:3, male, Chinese

CasePresentingHPOs HP:0007675, HP:0001123, HP:0000543, HP:0000572, HP:0007737, HP:0031609, HP:0008043

CaseMethod1 PCR

CaseGenotypingMethod genes related to opthalmological diseases

Variant NM_000087.3(CNGA1):c.265delC (p.Leu89Phefs) and novel "p.Y82X"

ClinVar (1st) 225315 link

CAID (2nd) CA356834547 link

gnomAD 0.001378 link

Case7: Male, 13 yrs report

CasePresentingHPOs: HP:0001288, HP:0003701, HP:0009053, HP:0000765, HP:0002650, HP:0001250, HP:0006466, HP:0003798, HP:0003803 (Abnormal gait, Proximal limb weakness, Distal lower limb muscle weakness, Abnormality of the chest, Scoliosis, Epilepsy, Ankle contracture, Nemaline bodies, Type 1 muscle fiber predominance)

HPOsFreeText: Jaw contracture

CaseNotHPOs: HP:0001627 (Cardiac abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Parental testing not performed

CasePreviousTesting: ACTA1 was sequenced and returned negative.

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

FamilyName: Family 2

FamilyPresentingHPOS: HP:0002497, HP:0003429

FamilyNotHPOs:

CountryOrigin: Kenya and Tanzania

Ethnicity: n/a

Race: n/a

FamilyPreviousTesting: MRI showed brain hypomyelination

FamilyGenotypingMethod: combination of homozygosity mapping and WES, haplotype analysis

Affected: 2

Unaffected:

Segregations:

PublishedLOD:

eLOD:

AddSegregationInfo:

ProbandLabel: III-2 (individual 4), Female, 44yo, dx at 1yo

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

CasePresentingHPOs: HP:0000639, HP:0002066, HP:0002061, HP:0001272, HP:0007366, HP:0002540, HP:0000473, HP:0002451, HP:0002599, HP:0000571, HP:0000666, HP:0000496, HP:0002078, HP:0002070, HP:0008969, HP:0001348

CasePresentingHPOTerm: nystagmus, gait ataxia, lower limb spasticity, cerebellar atrophy, brainstem atrophy, inability to walk, cervical dystonia, lower limb dystonia, head titubation, hypometric saccades, horizontal nystagmus, limited eye movements, truncal ataxia, limb ataxia, lower limb stiffness

CaseNotHPOs: HP:0011730

AddCaseInfo: Cousin with identical phenotype died due to tuberculosis in childhood. (Individual 5)

VariantEvidence:

Family 3

Variant, (NM_177400.2; c.487C>G; p.Leu163Val), replaces conserved leucine within the first helix of the homeodomain, therefore destabilizing the protein.

Case3: Male, 8 yrs onset, Australia

CasePresentingHPOs: HP:0009046, HP:0003701, HP:0003722, HP:0001488, HP:0002938, HP:0010628, HP:0030877, HP:0003803, HP:0003755 (Difficulty running, Proximal muscle weakness, Neck flexor weakness, Bilateral ptosis, Lumbar hyperlordosis, Facial palsy, Obstructive deficit on pulmonary function testing, Type 1 muscle fiber predominance, Type 1 fibers relatively smaller than type 2 fibers)

HPOsFreeText: Type 2B fibers absent

CaseNotHPOs: HP:0003798, HP:0030177, HP:0003391 (Nemaline bodies, Abnormal nerve conduction study, Gowers sign)

NotHPOsFreeText: N/A

CaseAddInfo: Variant is likely de novo, but there is no parental testing to confirm

CasePreviousTesting: Patients were diagnosed with CFTD via clinical notes and muscle biopsies at pathology centers throughout Australia and several international centers.

CaseGenotypingMethod: Two methods were used for genotyping. In 16 patients, the 10 exons spliced onto the muscle-specific isoform of TPM3 were bidirectionally sequenced from genomic DNA. For the other 7 patients, complementary DNA was generated from patient muscle and isoform-specific primers were used to sequence the transcript. Paternity was confirmed in isolated patients using microsatellite markers.

Variant: NM_152263.4(TPM3):c.502C>G (p.Arg168Gly)

ClinVar: 12453 https://www.ncbi.nlm.nih.gov/clinvar/variation/12453/

gnomAD: Not in gnomAD

Case: Individual 4, male, AOR= 8 yo

CasePresentingHPOs:  HP:0001518, HP:0004322, HP:0000252, HP:0001270, HP:0011344, HP:0002187HP:0000750, HP:0002069, HP:0002121, HP:0006829, HP:0100023, HP:0000735, HP:0000248, HP:0001357, HP:0000490, HP:0011229, HP:0000527, HP:0045025, HP:0003196, HP:0000414, HP:0000463, HP:0000288, HP:0000160, HP:0000219, HP:0000232, HP:0000307, HP:0000400, HP:0200055, HP:0001769, HP:0006045, HP:0004209, HP:0010610, HP:0001795, HP:0000193, HP:0003100, HP:0000938, HP:0002750, HP:0002205, HP:0000565, HP:0011968

CasePResentingHPOText: Subject began walking at 5 y.o. First words at 8 y.o. and noted as only having 2 words. Seizure onset at 3 y.o. with general tonic clonic seizures and absence. At 4 y.o. noted as having little social interaction, and intermittent hand flapping. Noted as having a feeding tube until age 8.

CaseNOTHPOs: HP:0002376, HP:0012443, HP:0002360

CasePreviousTesting: Affymetrix Cytogenetics 2.7 array testing was unremarkable.

CaseGenotypingMethod: Trio-WES. Testing also identified a de novo VUS in SMARCAD1 (NM_0011 28429.1):c hr4:g.9520 1881T>A, c.2563T>A, p.(Ser855Thr), this gene is associated with skin disease.

Variant: hg19:chr2: g.4804614 7G>C, c.1868C>G , p.(Thr623Arg) OR NM_001190274.1:c.1868C>G

CA ID: CA346764020

de novo Trio-WES performed so maternity and paternity could be investigated with this method.

gnomAD: n/a

AddCaseInfo:

VariantEvidence: Thr623 is located in the second CASH domain of FBXO11, and is conserved across specieis. These domains are responsible for the substrate recognition. Pathogenicity algorithms showing varying predictions, from tolerated to damaging, thus indicating a VUS. No functional assays were performed to indicate the impact of the T623R mutation on FBXO11 function.

Case# Xin II:6, Female, 42, Chinese

CasePresentingHPOs HP:0007663, HP:0007675, HP:0001133

CaseMethod1 Sanger Sequencing

CaseGenotypingMethod NGS

Variant NM_000087.3(CNGA1):c.265delC (p.Leu89Phefs), NM_000087.3(CNGA1)c.1537G>A(p.G513R)

ClinVar 225315(1st)

CAID CA2911062(2nd)

VariantEvidence p. G513R protein localized to cytoplasm instead of plasma membrane like wildtype (fig. 3)

Western blot of the variant in the proband NO-1 from previously published PMID: 20157015

Case# Li-AP:II-4, F, 19 report

CasePresentingHPOs HP:0002066, HP:0000639, HP:0001903, HP:0005528, HP:0001251, HP:0001260,

HPO free text: "A bone marrow biopsy at age 14 showed hypocellularity with normal karyotype. A marrow sample obtained at age 17 failed to yield mitotic cells for cytogenetic analyses, both on direct preparation and after culture for up to 48 hr. At age 54 years, she has developed moderately severe ataxia and requires a walker to ambulate. Her mental status is normal and she has mild horizontal and vertical nystagmus, dysarthria, dysmetria, bilateral Babinski responses, and mild decreased appreciation of vibration in her toes. Brain MRI at the age of 52 years showed severe diffuse cerebellar atrophy as well as diffuse bilateral white matter signals throughout the cerebrum."

CasePreviousTesting Clinical genetic testing ruled out abnormalities in an extensive panel of dominant cerebellar ataxia genes.

CaseMethod1 Sanger

CaseGenotypingMethod Targeted Sanger sequencing of the single large coding exon of SAMD9L

Variant NM_152703.4(SAMD9L):c.3587G>C (p.Cys1196Ser)

ClinVar 242373

CasePMIDs 6947857(1981)

Family#PresentingHPOs HP:0001251, HP:0001272

FamilyNotHPOs HP:0001903, HP:0004808, HP:0001876, HP:0005528

Family#PreviousTesting Studied blastogenic responses to pokeweed mitogen, phytohemagglutinin, and concanav~lin A and rate of unscheduled DNA synthesis in fibroblasts which were normal. II-5 karyotyping showed he had C-monosomy 7.

Family#Method1 Sanger Sequencing

Family#GenotypingMethod Targeted Sanger sequencing of the single large coding exon of SAMD9L

Affected 3

Unaffected 1

Segregations 2*

AddSegregationInfo

ProbandLabel Li-AP:II-4, F, 19 report

Variant NM_152703.4(SAMD9L):c.3587G>C (p.Cys1196Ser)

ClinVar 242373

FamilyAddInfo Italian Mother(asymptomatic), Polish Father and 3 brothers had cerebellar ataxia/atrophy. 2 brothers died with acute mylogenous leukemia, other died with pancytopenia and hypoplastic bone marrow

FamilyPMIDs 6947857

Case#: Consequence 27 Table 1 in Data Supplement (1 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.2609G>A (p.Arg870His)

ClinVar: 14120 https://www.ncbi.nlm.nih.gov/clinvar/variation/14120/

CAID: n/a

gnomAD: 0.00001549 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23894048-C-T

Case#: Consequence 19 Table 1 in Data Supplement (2 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.1491G>T (p.Glu497Asp)

ClinVar: 14124 https://www.ncbi.nlm.nih.gov/clinvar/variation/14124/

CAID: n/a

gnomAD: 0.0001984 Ashkenazi Jewish https://gnomad.broadinstitute.org/variant/14-23897796-C-A

Case#: Consequence 15 Table 1 in Data Supplement (1 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.2167C>T (p.Arg723Cys)

ClinVar: 14095 https://www.ncbi.nlm.nih.gov/clinvar/variation/14095/

CAID: n/a

gnomAD: 0.00003266 South Asian https://gnomad.broadinstitute.org/variant/14-23895023-G-A

Case#: Consequence 10 Table 1 in Data Supplement (2 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.1816G>A (p.Val606Met)

ClinVar: 14091 https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/

CAID: n/a

gnomAD: 0.00001548 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23896866-C-T

Case: Bolino Proband 1 (proband 1945), male, reported at 4yo, symptom onset at 42mo

CasePresentingHPOs: HP:0001349, HP:0003701, HP:0001284, HP:0001288, HP:0003474, HP:0003693, HP:0003722, HP:0003391, HP:0001761, HP:0003383, HP:0012447 (bilateral facial weakness, proximal muscle weakness, areflexia, abnormal gait, sensory impairment, distal limb muscle atrophy, neck flexor weakness, Gower's sign, pes cavus, onion bulb formation, abnormal myelination)

HPOsFreeText: walked at 14mo, eyes reported to be normal, gait - bilateral steppage, pes equinovarus deformity of both feet, frequent falling, had normal early motor milestones, bilateral pes cavus with retraction of Achille's tendon, intellectually normal. Laboratory testing normal: full blood count, fasting blood glucose, serum electrolytes, creatine kinase, lactic acid, urinary organic acids, serum and urine carnitine, EEG, ECG, and liver echography, segmental demyelination in 92% of fibers, redundant loops of myelin sheath irregularly arrayed near axon, muscle biopsy of rectus femoris showed atrophic and angulated fibers in clusters and large type grouping, lipid accumulation

Median nerve conduction studies: compound motor action potential = 4.6uV, distal motor latency = 7.8msec, sensory action potential = 3.3uV, motor nerve conduction velocity = 17msec, sensory nerve conduction velocity = 18msec

Peroneal nerve conduction studies: compound motor action potential = 0.21uV, distal motor latency = 7.8msec, motor nerve conduction velocity = 14

Sural nerve conduction studies: sensory action potential = no response, sensory nerve conduction velocity = no response

CountryOrigin: Italy

FamilyInfo: consanguineous family, parents reported to be normal at clinical and electrophysiological exams

PreviouslyPublished: PMID:10673338, PMID:8817346, PMID: 8628474, PMID: 8017168

GenotypingMethod: RT-PCR of RNA from patient lymphoblastoid cell line, available family members analyzed and segregation of variant with disease confirmed in pedigree - PMID:8817346 - homozygosity mapping and haplotype sharing through microsatellite and linkage analysis

Variant: NM_016156.5(MTMR2):c.1276C>T (p.Gln426Ter) homozygous

ClinVar: 6231, https://www.ncbi.nlm.nih.gov/clinvar/variation/6231/

gnomAD: 0.000007085, https://gnomad.broadinstitute.org/variant/11-95578227-G-A

Case#: Patient #6, male, 22yo

DiseaseAssertion: MPS1, Hurler-Scheie Syndrome

FamilyInfo:

CasePresentingHPOs: HP:0033834, HP:0012378, HP:0001387, HP:0006536, HP:0002719, HP:0001433, HP:0001510, HP:0007957, HP:0010535, HP:0004749, HP:0002094, HP:0000969, HP:0003541, HP:0001537, HP:0000023

CaseHPOFreeText: NYHA class IV at beginning of therapy, cardiac valve disease

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: physical examination including history-taking, magnetic resonance imaging of the abdomen and brain, and range-of-motion measurements. Echocardiography and electrocardiography were performed at base line and at 12, 26, and 52 weeks. Corneal photographs were obtained and a skeletal survey was performed at base line and at weeks 26 and 52. A skin biopsy was performed at base line to establish cultures of fibroblasts for the determination of enzyme activity and genotyping. Biochemical studies included measurement of enzyme activity in leukocytes and brushings of buccal mucosa, urinary glycosaminoglycan excretion, and tests for serum antibodies to α-L-iduronidase.

GenotypingMethod:

PreviouslyPublished:

Variant: 236C>T, compound het with c.1727+2T>A (CA355965298)

ClinVar: 1458769

CAID:

gnomAD: n/a

SupplementalData:

Case: Family F Proband FII-6, female, Arabic, Israeli, 27yo at report

CasePresentingHPOs: HP:0000953, HP:0030053, HP:0000998, HP:0002619, HP:0000520, HP:0007380, HP:0100324, HP:0100727

CasePresentingHPOsFreeText: dilated scleral vessels

CaseNOTHPOs: HP:0008064, HP:0001433, HP:0011025, HP:0000365, HP:0012385

CaseNOTHPOSFreeText:

CasePreviousTesting: direct sequencing of AIFM2, ADAMTS14, EIF4EBP2, C10ORF54, PPA1, H2AFY2, LRRC20, NODAL, PRF1, TYSND1, SAR1A, PSAP, NPFFR1, and C10ORF27

CaseGenotypingMethod: microarray, haplotype analysis, direct sequencing of exons of SLC29A3, restriction digestion

Variant: G437R homozygous

ClinVarID: or CAID: 565/CA114352

gnomAD: The missense variant G437R is present in gnomAD v4.0.0 with a MAF=0.00006666 (4/60002 alleles) in the Admixed American population and 0 homozygotes.

AddCaseInfo: consanguineous parents, not genotyped. brother (FII-5) is het and unaffected.

PreviouslyPublished: PMID: 18410979

VariantEvidence: Kang et al. (2010; PMID: 20595384) performed functional characterization of the G437R mutation in Xenopus oocytes and observed transport activity that was approximately half that of wildtype SLC29A3. Studies in NIH 3T3 fibroblasts demonstrated accelerated turnover of the G437R mutant compared to wildtype, suggesting decreased stability.

Case#: Family FR-1, 30yo, male, French

DiseaseAssertion: DOA+

FamilyInfo: positive family history, but no information provided

CasePresentingHPOs: HP:0000648, HP:0000365, HP:0001251, HP:0003198, HP:0001138

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

GenotypingMethod: The entire OPA1-coding region and flanking exon–intron boundaries were amplified by the polymerase chain reaction (PCR) and sequenced with BigDye terminator cycle chemistries on an appropriate genetic analyser. All genetic variants were confirmed by reverse sequencing

Variant: c.1635C>G (p.S545R) aka c.1800C>G (p.S600R)

ClinVar: 30461

CAID: CA10575554

SupplementalData:

Case#: Li 2018 sALS I243T, Chinese, 51 y.o. onset

MonDO: MONDO:0005145 for sALS

CasePresentingHPOs: HP:0007354

CaseGenotypingMethod: Sanger sequencing. TUBA4A sequencing was performed using Sanger. No further details provided.

Variant: NM_006000.3(TUBA4A):c.701T>C (p.Ile234Thr)

CAID: CA350726345

Case: Kameli Proband, male, 4yo at dx, Iran

CasePresentingHPOs: HP:0000256, HP:0000271, HP:0100540, HP:0001537, HP:0045075, HP:0000348, HP:0012811, HP:0000286, HP:0000494, HP:0000343, HP:0000308, HP:0012471, HP:0000280, HP:0000212, HP:0006288, HP:0001763, HP:0000974, HP:0005692, HP:0000978, HP:0001053, HP:0002500

CasePresentingHPOsFreeText: hypopigmented skin lesion under anterior abdominal region around umbilicus. Brain MRI revealed diffuse abnormal white matter signals high in long TR sequence more pronounced at superficial subcortical and deep peritrigonal regions at the level of basal ganglia and centrum semiovale in T2 weighted spin echo and FLAIR sequence images. In addition, bilateral anterior temporal small subcortical cysts formation and increased perivascular spaces on posterior deep white matter were noticed clearly in T2 weighted and FlAIR sequence images.

CaseNOTHPOs: HP:0001270, HP:0000750, HP:0000707, HP:0008064, HP:0002650

CaseNOTHPOSFreeText:

CasePreviousTesting:

CaseGenotypingMethod: WES, Sanger

Variant: NM_001242581.1: c.2251dup; p.(Leu751Profs*9); homozygous

ClinVarID: or CAID: 590794

gnomAD: This proband has a frameshift variant, p.Leu702fs, in exon 11/13 that is absent from gnomAD v2.1.1.

AddCaseInfo: second child born to a consanguineous marriage; parents were heterozygous carriers

PreviouslyPublished: n/a

VariantEvidence: n/a

FamilyLabel PcTas72

Family#PresentingHPOs HP:0012125 (Prostate cancer)

FamilyNotHPOs n/a

CountryOrigin Tasmania

Ethnicity n/a

Race n/a

Family#PreviousTesting n/a

ProbandLabel 154, male, 63yo diagnosis

Variant NM_006361.5(HOXB13):c.251G>A (p.Gly84Glu)

ClinVar 128031

gnomAD MAF=0.007574(European(Finnish)), 2 homozygotes

FamilyAddInfo Variant did not segregate with disease on 3rd branch of family. Three genotype negative males on the 3rd branch presented with prostate cancer.

FamilyPMIDs n/a

CaseP785: Male, 10 yrs onset

CasePresentingHPOs: HP:0007340, HP:0007210, HP:0002495, HP:0001639 (Lower limb muscle weakness, Lower limb amyotrophy, Impaired vibratory sensation, Hypertrophic cardiomyopathy)

HPOsFreeText: Wheelchair-bound 25 yrs

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: 21.8% fratraxin protein levels

CaseGenotypingMethod: See Group

Variant1: FXN, (GAA)n REPEAT EXPANSION, IVS1

ClinVar: 561195, https://www.ncbi.nlm.nih.gov/clinvar/variation/561195/

gnomAD: Not in gnomAD

Variant2: NM_000144.5:c.99del (p.Ala34ProfsTer?)

CAID: CA193369008, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA193369008

gnomAD: Not in gnomAD

CaseP585: Male, 14 yrs onset

CasePresentingHPOs: HP:0002078, HP:0001152, HP:0000639, HP:0007340, HP:0007210, HP:0002495, HP:0001639 (Truncal ataxia, Saccadic smooth pursuit, Nystagmus, Lower limb muscle weakness, Lower limb amyotrophy, Impaired vibratory sensation, Hypertrophic cardiomyopathy)

HPOsFreeText: Wheelchair-bound 22 yrs

CaseNotHPOs: HP:0000648, HP:0000365, HP:0001760, HP:0002015 (Optic atrophy, Hearing impairment, Abnormal foot morphology, Dysphagia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: 19.4% fratraxin protein levels

CaseGenotypingMethod: See Group

Variant1: FXN, (GAA)n REPEAT EXPANSION, IVS1

ClinVar: 561195, https://www.ncbi.nlm.nih.gov/clinvar/variation/561195/

gnomAD: Not in gnomAD

Variant2: NM_000144.5:c.354C>G (p.Tyr118Ter)

CAID: CA193385376, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA193385376

gnomAD: Not in gnomAD

PMID: 12721840

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Case1049: 5 yrs onset, United States, Black

CasePresentingHPOs: HP:0006785, HP:0003236 (Limb-girdle muscular dystrophy, Elevated serum creatine kinase)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Affected brother, sister, and half-brother, Genotype confirmed in proband and affected brother only

CasePreviousTesting: Serum CK levels 8,000 - 18,000 UI/l; Genetic testing also included DMD, FKRP, DM1, DM2;

CaseGenotypingMethod: DNA was collected from peripheral blood or saliva samples. WES was performed and processed though a pipeline before aligning the reads and analyzing the candidate gene list for any variants using the various inheritance patterns. Screening was performed based on in silico predictors with a liberal threshold to filter variants before PCR amplification and Sanger sequencing confirmed the pathogenic mutations.

Variant1: NM_000231.2(SGCG):c.195+4_195+7del

ClinVar: 208611 https://www.ncbi.nlm.nih.gov/clinvar/variation/208611/

gnomAD: 0.00004009, https://gnomad.broadinstitute.org/variant/13-23778027-CAGTA-C

Variant2: NM_000231.2(SGCG):c.195+1G>C

ClinVar: 283707 https://www.ncbi.nlm.nih.gov/clinvar/variation/283707/

gnomAD: 0.0002004, https://gnomad.broadinstitute.org/variant/13-23778029-G-C

Case# Tadic Index, F, Turkish, 39yo report

CasePresentingHPOs HP:0001260, HP:0000514, HP:0001285, HP:0001276, HP:0001776, HP:0002070, HP:0002317

CasePreviousTesting The patient scored 4/40 on the Scale for the Assessment and Rating of Ataxia (SARA). Baclofen, tizanidine and tolperisone were not tolerated or inefficacious but she responded to botulinum toxin injections with a mean improvement of 40–50%. Her cranial MRI showed very mild cerebellar vermal atrophy, whereas spinal cord imaging was unremarkable

CaseMethod1 Whole Exome

Variant NM_001198869.1:c.759+1G>A

CAID CA381244789

gnomAD 0.00006707(African), 0.000004189(Overall)

VariantEvidence splice-site variant

CaseAddInfo in trans

From supplemental tables S2 and S3 (authors used hg19 alignment).

MONDO: MONDO:0005144 for FALS

Case#5: Smith 2014 FALS R320H, F, 41 y.o. onset, Italy

CasePresentingHPOs: HP:0007354

CaseHPOFreeText: spinal-onset ALS with upper and lower motor neuron signs

CasePreviousTesting: All FALS were screened for known causative mutations/repeat expansions in SOD1, C9orf72, TARDBP, FUS, PFN1, UBQLN2, OPTN, VCP and ANG and removed from cohort if positive for variant.

CaseMethod1: This case identified through case-control study

CaseGenotypingMethod: Exome sequencing, confirmed with Sanger sequencing.

Variant: NM_006000.3(TUBA4A):c.959G>A (p.Arg320His)

ClinVar: 180183

gnomAD: 2-220115462-C-T; Total overall AF (non-neuro) = 0.000 ; TUBA4A_p.Arg320His_gnomAD

CaseAddInfo: This variant found in 0/13023 control samples.

From supplemental tables S2 and S3 (authors used hg19 alignment).

MONDO: MONDO:0005144 for FALS

Case#2: Smith 2014 FALS, T145P, M, 69 y.o. onset, Italy

CasePresentingHPOs: HP:0007354

CaseHPOFreeText: spinal-onset ALS with upper and lower motor neuron signs

CasePreviousTesting: All FALS were screened for known causative mutations/repeat expansions in SOD1, C9orf72, TARDBP, FUS, PFN1, UBQLN2, OPTN, VCP and ANG and removed from cohort if positive for variant.

CaseMethod1: This case identified through case-control study

CaseGenotypingMethod: Exome sequencing, confirmed with Sanger sequencing.

Variant: NM_006000.3(TUBA4A):c.433A>C (p.Thr145Pro)

ClinVar: 180187

CaseAddInfo: This variant found in 0/13023 control samples.

Article is a PDF, so annotating here.

Case#: Atceken Patient 10, Turkey

DiseaseAssertion: MPS1, Hurler

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: n/a

GenotypingMethod: All IDUA exons were amplified using intronic primers flanking the exonic nucleotide sequences by direct DNA sequencing of PCR products, segregation analysis

PreviouslyPublished: n/a

Variant: p.R628X homozygous

ClinVar: 550421

CAID: CA2802462

gnomAD: The highest population minor allele frequency in gnomAD v4.1.0. is 0.00005038 (2/39700 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).

SupplementalData: n/a

Proband KH3 was 13yo at report, has the Hurler phenotype, and has this variant in compound heterozygosity with second missense variant on exon 3, but that variant is not provided.

This variant is mentioned as top recurrent variant and refers to several studies that have already been included in the curation. No new data.

PMID 19535918 Gene: UNC80

Patient: ID266

Variant: c.685delG

CAID: CA2580612031

Functional effect: Normal exon inclusion (band A) *, exon 4 skipping (band B), exon 4 + 5 skipping. Observed in blood.

Case 3: HP:0001639, underwent myectomy and ICD, two sons with neg echos, family history - mother died at 84, NM_005655.3:c.409G>A (p. Glu137Lys), gnomAD= 8.152e-6, Euro(Nf)=1.801e-5)

Case#: Yamagishi Case 2, female, 10mo, Japanese

DiseaseAssertion: MPS1-Hurler

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: mental delay, height -1.5SD

CaseNotHPOs:

CaseNotHPOFreeText: cardiac involvement

PreviouslyPublished: n/a

Variant: 704ins5 homozygous

ClinVar: 11921

CAID: CA256123

SupplementalData: n/a

Case#: KMP 18, female, 71 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: symptomatic; LVEF 60%; NYHA I.-II.; ECG; echocardiography;

CaseNotHPOs: n/a

CaseNotHPOFreeText: no LVOTO; no ICD

CasePreviousTesting: Additional Sanger sequencing of exons 12, 24, 25 of MYBPC3, exon 12 NEBL, exons 12, 20, 21 of SCN5A, exon 7 of TNNI3, and exon 9 of TNNT2 gene

CaseGenotypingMethod: Sanger sequencing;

Variant: NM_000257.4(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093 https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

CAID: n/a

gnomAD: absent

PMID: 26399558

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

InheritancePattern: X-linked

PMID: 28132690

Gene: EXTL3

Disease: Neuro-immuno-skeletal Dysplasia Syndrome

MonDO ID: n/a

OMIM: 617425

RescuePatientCell CL:0000057

GeneAlteration NM_017819.3(TRMT10C):c.814A>G (p.Thr272Ala) and/or NM_017819.3(TRMT10C):c.542G>T (p.Arg181Leu)

RescuePhenotype defective oxidative phosphorylation and tRNA 5' processing affecting high energy demand tissues: HP:0001508 (Failure to thrive)

RescueMethod Fibroblasts transfected with lentiviral vector containing single copy of WT TRMT10C.

RescueEvidence Transfected patient cells had increased MRPP1 expression, restored mitochondrial translation, normalized levels of respiratory chain complexes and mt-tRNA precursors which rescues the reduced cellular oxidative phosphorylation and slowed growth. 21857155 demonstrates both the restriction of translation and reduction of the rate of oxidative phosphorylation during MRPP1 knockdown in HeLa cells (Fig 5). Those result corroborate the gap between reduced MRPP1 expression and reduction in translation of oxidative phosphorylation machinery.

RescueVariants n/a

PMID: 28708303 Gene: UNC80

Case#: 10014, Female, Caucasian, 47 years (onset), 70 years (report)

CaseHPOs: HP:0000643, HP:0012048 (Blepharospasm, oromandibular dystonia)

CaseHPOFreeText: Segmental dystonia (blepharospasm, oromandibular, lower face)

CaseNotHPOs:

CasePreviousTesting: Prior to WES, pathogenic variants in THAP1, GNAL, and Exon 5 of TOR1A were excluded by high resolution melt analysis.

CaseMethod1: WES

CaseMethod2: Confirmation by Sanger sequencing

CaseGenotypingMethod:

Variant: NM_020821.2:c.10954C>T (p.Arg3652Ter)

ClinVar: N/A

CAID: CA7594135

gnomAD: 0.0002887 (European non-Finnish); no homozygotes

VariantEvidence: None

Case: Male, 15 yrs onset

CasePresentingHPOs: HP:0002875, HP:0001639, HP:0009073, HP:0003551, HP:0001962, HP:0004749, HP:0003758, HP:0003306, HP:0003712, HP:0003691, HP:0003184, HP:0002515, HP:0001265, HP:0003236, HP:0003458, HP:0012548, HP:0031295, HP:0006699, HP:0002375, HP:0012664, HP:0001685, HP:0032341, HP:0003557 (Exertional dyspnea, Hypertrophic cardiomyopathy, Progressive proximal muscle weakness, Difficulty climbing stairs, Palpitations, Atrial flutter, Reduced subcutaneous adipose tissue, Spinal rigidity, Skeletal muscle hypertrophy, Scapular winging, Decreased hip abduction, Waddling gait, Hyporeflexia, Elevated serum creatine kinase, EMG: myopathic abnormalities, Fatty replacement of skeletal muscle, Left atrial enlargement, Premature atrial contractions, Hypokinesia, Reduced ejection fraction, Myocardial fibrosis, Reduced forced vital capacity, Increased variability in muscle fiber diameter)

HPOsFreeText: Difficulty lifting heavy objects, Unable to get up from the floor or stand up from a chair without support

CaseNotHPOs: HP:0000822, HP:0030319, HP:0007715 (Hypertension, Weakness of facial musculature, Weak extraocular muscles)

NotHPOsFreeText: N/A

CaseAddInfo: RT-PCR analysis indicated complete absence of TRIM63 transcripts in the proband indicating NMD, with TRIM54 expression found in muscle tissue and cultured cells

CasePreviousTesting: Treated with diltiazem 200 mg daily because he did not tolerate betablockers owing to asthenia; There were single or multiple well-circumscribed non-membrane-bound subsarcolemmal deposits in the majority of type I fibres, with partial colocalization to MyHC and MuRF3; Tested for mutations in MYH7 and gene panel involved in familial HCM (genes not provided)

CaseGenotypingMethod: Sanger sequencing was performed for the proband due to similarities found in MuRF1/MuRF3 null mice, with a homozygous nonsense variant in TRIM63 and heterozygous missense variant in TRIM54 being found. To exclude any other potential disease-causing variants, WES was performed and filtered down to nine genes with only these variants encoding muscle-specific proteins.

Variant: NM_032588.3(TRIM63):c.739C>T (p.Gln247Ter)

ClinVar: 222849, https://www.ncbi.nlm.nih.gov/clinvar/variation/222849/

gnomAD: 0.008100, https://gnomad.broadinstitute.org/variant/1-26384973-G-A?dataset=gnomad_r2_1

RescueModel: Rescue WT CAG::GALNS in murine model by ovexpression in a Galns variant frequently found in human's affected with MPSIVA

GeneAlteration: transduction by AAV9 of CAG promoted WT murine optimized Galns coding sequence. Widespread tissue transduction was visualized with a CAG promoted GFP cassette delivered by AAV9, subsequently GFP production was widespread and found in all relevant tissue including osteoblast rich areas.

RescueVariant: AAV9-Galns with the coding sequence under the control of a CAG promoter element

RescuePhenotype: HP:0004325, MP:0001258, HP:0005736

RescueMethod: p.Arg386Cys (MPSIVA) mice were first transducted with CAG::GFP via AAV9 to verify efficiency of delivering the coding sequence to target tissue like bone. Then a CAG::Galns (optimized WT) was transducted in to MPSIVA mice (Galns -/-) via AAV9 by 4 weeks of age to avoid the high mortality in the Galns homozygote starting at 2 months.

RescueEvidence: Early transduction of Galns -/- mice recovered higher than WT enzyme activity and WT levels of keratan sulfate detected in liver tissue. Abnormalities in the growth plate in Galns -/- mice were absent in those treated with AAV9-Galns resulting from a return to WT levels of enzyme activity and keratan sulfate in all bone tissue sampled. GALNS activity recovered in lung and heart tissue with the elevated heart rate in MPSIVA mice returned to WT.

ModelVariant: p.Arg386Cys

PMID: 36245961

Gene: GALNS

Disease: Mucopolysaccharidosis IVA/ Morquio A

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

Case#: Perrone 2017, F, 47 y.o. onset, Belgium

CasePresentingHPOs: HP:0007354, HP:0009027, HP:0001260, HP:0007289, HP:0001324, HP:0003487

CasePreviousTesting: Multiplex exome NGS panel for major FTD, ALS, AD, and PD genes: GRN, MAPT, VCP, TARDBP, FUS, SOD1, TBK1, APP, PSEN1, PSEN2, PRNP, LRRK2, PARK2, and SNCA

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: Whole-genome sequencing, exome resequencing using a multiplex NGS panel for major FTD, ALS, AD, and PD genes, and multiplex PCR amplification of the 4 TUBA4A exons (if all patients from the "Belgian Neurology consortium" are also the "patients of Project MinE").

Variant: NM_006000.3(TUBA4A):c.1142C>T p.Thr381Met

CAID: CA2122379

gnomAD: 2-220115279-G-A, Total overall AF (non-neuro) = 0.00001922; TUBA4A_Thr381Met_gnomAD

CaseAddInfo: The reported variant c.1142G>A is not a valid allele for TUBA4A. That is the genomic coordinate of the reference, not the coding sequence (TUBA4A is on the antisense strand). The CAID was found using fuzzy query at the protein level.

Family#PresentingHPOs HP:0007994, HP:0007675

CountryOrigin Pakistan

Ethnicity NonHispanic/Latino

Race White

Family#PreviousTesting

Family#Method1 WES

Family#Method2 Sanger

Family#GenotypingMethod Sanger of IRD associated genes, SNP array analysis

Affected 3

Unaffected 3

Segregations 3

eLOD 1.50

ProbandLabel Maleeha 2:1, Female, White

Variant NM_000087.3(CNGA1):c.1298G>A(p.G433D)

CAID CA2911103

gnomAD 0.000008974 link

Case1: 58 year old female

DiseaseAssertion: HCM

FamilyInfo: proband's daughter presents with same disease and mutation

CasePresentingHPOs: HP:0008994, HP:0000218

"Proximal muscle weakness in lower limbs, High palate

CaseHPOFreeText: symmetrical bilateral ptosis without oculomotor palsy, high arched palate but the rest of the cranial examination was normal, weakness of neck flexors, weakness in psoas and tibialis anterior, unable to walk on heels

CaseNotHPOs: n/a

CaseNotHPOFreeText: atrophy of the sternocleidomastoid muscles, hanging big toe

CasePreviousTesting: n/a

GenotypingMethod: "gene sequencing"

Variant: NM_000257.4:c.746G>A

ClinVar: 14088

CAID: CA016781

gnomAD: not found

PMID: 35729508

Gene: GALNS

Disease: Mucopolysaccharidosis Type IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes: Case Study - 23 probands

11704930 connects these cases to CASQ2

Variant NM_001232.3(CASQ2):c.919G>C (p.Asp307His)

ClinVar 17610

gnomAD 0.00003249 link

PMID: 12090986

Gene: TERC

Disease: Dyskeratosis congenita & bone marrow failure/pulmonary fibrosis

MonDO: MONDO:0007485, MONDO:0013879

InheritancePattern: AD

Notes: variants: NR_001566.1:n.58G>A, NR_001566.1:n.72C>G, NR_001566.1:n.110_113del

Case: CP, 37 years, female

CasePresentingHPOs: HP:0003563 (reduced LDL-cholesterol level)

CasePresentingHPOsFreeText:* Plasma cholesterol and triglyceride levels for CP were below the 5th percentile; total cholesterol 2.61 (normal range 4-6.5 mmol/l), triglyceride 0.36 (normal range 0.3-1.8 mmol/l), apoB 9 (normal range 60-140 mg/dl, on Vitamin E supplement.

PresentingNotHPOs: HP:0001927 (acanthocytosis)

CaseGenotypingMethod: Genomic DNA was digested with a panel of restriction enzymes and Southern blotted. CP was heterozygous for a loss of a TaqI restriction site change which was localized to exon 25 by the hybridization pattern on Southern blot. ChP, her son, was also heterozygous. Genomic DNA in that region was amplified by the polymerase chain reaction (PCR), cloned, and sequenced.

Variant: NM_000384.3(APOB):c.3997C>T (p.Arg1333Ter), heterozygous

ClinVar: 17883

gnomAD: Not in gnomAD

CaseAddInfo: Patient is the mother of ChP who is under investigation for fat malabsorption. ChP is heterozygous for the variant c.3997C>T (p.Arg1333Ter). No abnormal i.e. truncated apoB was detected on Western blot of protein from VLDL/chylomicron, LDL, HDL or infranate fractions for CP.

Family#PresentingHPOs HP:0001263, HP:0002342, HP:0002465, HP:0000729, HP:0001290, HP:0002370, HP:0000574, HP:0000426, HP:0000426, HP:0000637, HP:0000675, HP:0000664, HP:0000545, HP:0001763

FamilyNotHPOs

CountryOrigin Pakistan

Ethnicity

Race

Family#PreviousTesting None

Family#Method1

Family#Method2

Family#GenotypingMethod three affected individuals (V-1, V-3, V-5) and four unaffected individuals (IV-7, IV-8, V-4 and V-6) were genotyped using the Illumina HumanOmniExpress BeadChip.

KaryoStudio program from Illumina Inc. was used to exclude cytogenetic abnormalities, and HBD mapping was performed by using the HomozygosityMapper.

whole exome capturing and sequencing in two affected individuals (V-1 and V-5) identified 1bp deletion at c.6879delT. confirmed by Sanger in affecteds and unaffecteds.

Exclusion of LOF variants in other genes per SFARI gene list.

Potential candidate variants were further validated in additional family members, and Pakistani population controls through Sanger sequencing

Affected 3

Unaffected 2

Segregations 2

PublishedLOD No

eLOD 1.45

AddSegregationInfo Unaffected parents and two unaffected siblings genotyped along with the 3 affected individuals.

ProbandLabel ATM02_V-3

Variant NM_017890.4:c.6879delT

ClinVar

CAID CA4824093

gnomAD 0.00003250 (South Asian)

FamilyAddInfo 3 affected brothers clinically evaluated. 1 underwent biochemical testing.

PatientID: DII2

KindredID: D

Case: M, 37Y0M (deceased), Chinese

DiseaseAssertion: hemangioblastoma

FamilyInfo: A 3-generation family is given with 3 confirmed members with this mutation. 2 other members had VHL-presenations however had not been tested for the gene.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: died of multiple central nervous system hemangioblastoma at the age of 37 without operation.

CaseNotHPOs: HP:0002666; HP:0009711; HP:0001737; HP:0005584 (pheochromocytoma, retinal capillary hemangioma, pancreatic cysts, renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F76del (c.226_228delTTC) [assumed]

LegacyVariant: p.F76del (c.439delTCT)

CaseProblemVariantFreeText: NM_000551.3:c.226_228delTTC automaps to NM_000551.3:c.227_229delTCT

ClinVarID: N/A

CAID: CA357012 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.226_228delTTC

gnomAD: N/A

VariantEvidence: No genetic testing was done prior to death, however family history and presentation leads to this assumption

MutationType: inframe_deletion

CivicName: F76del (c.227_229delTCT)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 2

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0001732; HP:0005584 (Hemangioblastoma, Abnormality of the pancreas, Renal cell carcinoma)

CaseHPOFreeText: CNS hemangioblastoma, renal cell carcinoma and pancreatic tumor or cyst (unspecified).

CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8634692

SupplementalData: N/A

Variant: p.F76del (c.227_229del)

LegacyVariant: c.437_439del

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229del

gnomAD: N/A

VariantEvidence: Variant reported as c.437_439del and mapped to c.224_226del which is equivalent to c.227_229del.

MutationType: inframe_deletion; deletion

CivicName: F76del (c.224_226delTCT)

MultipleGeneVariants: N/A

PatientID: 37

KindredID: 37

Case: Age, sex, ethnicity unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+1G>A

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223190 https://www.ncbi.nlm.nih.gov/clinvar/variation/223190/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Site (c.340+1G>A)

MultipleGeneVariants: N/A

PatientID: II-7

KindredID: 1

Case: M, Age Unknown, Turkish

DiseaseAssertion: asymptomatic

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. One additional member (II-9) had passed before testing however were likely a carrier of the mutation. This patient’s 3 siblings had the mutation, one of her children, and more. See Fig. 1 for full family pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: None - described as a carrier of the p.A149S mutation, with no clinical manifestations. Their asymptomatic work up could have been due to the individual's young age

CaseNotHPOs: N/A

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

PatientID: None

KindredID: 8

Case: M, 38Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Thirteen unrelated patients with germline VHL mutations who were diagnosed with VHL disease were evaluated.

CasePresentingHPOs: HP:0006880; HP:0001737; HP:0000107; HP:0002172; HP:0001288 (Cerebellar hemangioblastoma, Pancreatic cysts, Renal cyst, Postural instability, Gait disturbance)

CaseHPOFreeText: At 38Y, this patient showed mild imbalance with gait difficulty. MRI of the brain revealed a cystic mass in the cerebellum, which was pathologically found to be hemangioblastoma. When this patient underwent CT, which included the pancreas and kidney, multiple pancreatic cysts and renal cysts were found. 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: N/A

SupplementalData: N/A

Variant: c.464-1G>T

LegacyVariant: N/A

CaseProblemVariantFreeText: 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; missense_variant;transversion

CivicName: Splice Site (c.464-1G>T)

MultipleGeneVariants: N/A

PatientID: Carrier 11 (father to proband 7)

KindredID: 3

Case: M, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: Father, mother and sister (all relative to proband 7) had this variant. Both father and sister were asymptomatic. Proband and mother presented with unilateral PCC.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P138Afs*6 (c.410dup)

LegacyVariant: 623insTTTGTtG

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432421860, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.410dup

gnomAD: N/A

VariantEvidence: The VHL NM_000551.3 reference sequence surrounding nucleotide 410 is a TTTGTG sequence, where the 4th T is at position 410, which converts to nucleotide 623 in the legacy reference sequence (AF010238.1). Therefore it is assumed that the authors reported their insertion variant in the legacy nomenclature and this was mapped to p.Pro138Alafs*6 (c.410dup) in NM_000551.3.

MutationType: insertion; plus_1_frameshift_variant

CivicName: P138fs (c.410dup)

MultipleGeneVariants: N/A

PatientID: Carrier 6 (nephew to proband 3)

KindredID: 1

Case: M, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: The family with PCCs includes 56 members of 4 generations, and is from Gansu Province. Among them, 7 extended over 3 generations were diagnosed as PCCs. One died before admission and another died due to a cardiovascular incident. Five were initially evaluated; evaluation included medical history, physical examination, abdominal ultrasonography, CT or MRI and laboratory tests. All 5 probands of this family underwent surgical resection. The tumors were benign under pathological examinations. There were no recurrence and malignant transformation over the period of up to 23-year follow-up. Twenty members, including 5 live patients and 15 direct relatives, accepted genetic examination.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H125P (c.374A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223201, https://www.ncbi.nlm.nih.gov/clinvar/variation/223201/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: H125P (c.374A>C)

MultipleGeneVariants: N/A

A case report revealed a 12Y Pacific Island boy with bilateral pheochromocytoma at age 10Y. Genetic analysis of 3 exons of the VHL gene revealed a germline VHL mutation (p.Pro103His). The mother was screened for VHL genetic mutations and the same mutation was found. The mother was not screened for VHL symptoms at the time of paper publication. ACMG: PP4

GroupID: 15

Case: 23Y0M, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation was found in 1 VHL family with a single patient.

CasePresentingHPOs: HP:0009711; HP:0006880 (retinal capillary hemangioma; cerebellar hemangioblastoma)

CaseHPOFreeText: patient had retinal angiomas at 21Y and cerebellar hemangioblastomas diagnosed at 23Y

CaseNotHPOs: HP:0005584; HP:0002666 (renal cell carcinoma; pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.F91* (c.272_273delinsAA)

CaseProblemVariantFreeText: c.272T>A and c.273C>A results in c.272_273delinsAA

LegacyVariant: N/A

ClinVarID: CA2499307077 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499307077

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: delins; stop_gained

CivicName: F91* (c.272_273delinsAA)

MultipleGeneVariants: N/A

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangoblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. Southern blot and/or MLPA analysis by whole blood detected this mutation (c.164_165insG) which causes a frameshift and truncation allele. It was recorded here in 1 VHL family with 10 affected members. 7 had retinal angiomas, 3 has cerebellar hemangioblatomas, 2 had RCC and 3 had pheochromocytomas.

GroupID: 6

Case: 31Y0M, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation (c.182_185delCCGT) was found in 1 VHL family with a single patient.

CasePresentingHPOs: HP:0009711; HP:0006880 (retinal capillary hemangioma; cerebellar hemangioblastoma)

CaseHPOFreeText: patient had retinal capillary hemangioma diagnosed at 31Y and cerebellar hemangioblastoma diagnosed at 30Y

CaseNotHPOs: HP:0005584; HP:0002666 (renal cell carcinoma; pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.P61Rfs*5 (c.182_185delCCGT)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA658820712 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.182_185del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: P61FS (c.182_185delCCGT)

MultipleGeneVariants: N/A

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). This missense mutation (c.509T>G), affecting residue on the surface of pVHL, was found in a VHL family of 4, 3 with retinal hemangioblastomas, 1 with renal cell carcinoma diagnosed at 33Y, and 1 with pheochromocytoma diagnosed at 29Y. This mutation was reported in the paper with an incorrect cDNA written as c.509T>C, however correct translation should be c.509T>G given the Latif et al. (1993): c.722T>G (Val170Gly)

GroupID: 53

DiseaseAssertion: assumed VHL

GroupSize: 8

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 8 of the 573 patients discussed in this paper were found to have identical variants. This mutation (S65W (c.194C>G)) was found in 1 VHL family with 8 patients.

GroupPresentingHPOs: HP:0009711; HP:0006880; HP:0005584 (retinal capillary hemangioma, cerebellar hemangioblastoma, renal cell carcinoma)

GroupHPOFreeText: 6 had retinal hemangioblastoma, 5 had cerebellar hemangioblastomas, and 1 had renal cell carcinoma. Mean ages for each diagnosis follows: 32 (RH), 39 (CHB), 56 (RCC - with one patient)

GroupNotHPOs: HP:0002666 (pheochromcytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.S65W (c.194C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 43597 https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65W (c.194C>G)

MultipleGeneVariants: N/A

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (R82_V84del (c.243_251del)) was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 35CA. It was reported in the paper as c.456delRVV due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.

GroupID/ KindredID: 141CA

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 141CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L188Rfs*14 (c.563delT)

LegacyVariant: FS (c.776delT)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432423679 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.563delT

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site either by truncating the protein or by location between codons 157 and 189.

MutationType: minus_1_frameshift_variant

CivicName: L188fs (c.563delT)

MultipleGeneVariants: N/A

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (c.464-2A>C) was taken from the Bristol Myers Squibb database, with an unknown number of members belonging to Family ID 4BMS. It was reported in the paper as c.677-2A>C due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (H115Y (c.343C>T)) was taken from the Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 59CE. It was reported in the paper as c.556C>T due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.