Patient7: Male

CasePresentingHPOs: HP:0002194

HPOsFreeText: ERT dosage = 20 mg/kg/2 w, CRIM positive

CaseNotHPOs: HP:0004887

NotHPOsFreeText: no reversal of HCM

CaseAddInfo: Symptom onset and diagnosis at 3mo, ERT at 4mo, ERT lasted for 24mo, died at 28mo

CasePMIDs: 22644586, 14695532

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.655G>A (p.Gly219Arg)

ClinVar: 189065, https://www.ncbi.nlm.nih.gov/clinvar/variation/189065/

gnomAD: 1.666e-05, http://exac.broadinstitute.org/variant/17-78079656-G-A

Patient11: Female

CasePresentingHPOs: HP:0004887, HP:0002100, HP:0006597, HP:0200136, HP:0011471

HPOsFreeText: ERT dosage = 40mg/kg/w, HCM reversal, CRIM positive, able to run, diaphragmatic paralysis required plication at 3yo

CaseNotHPOs: HP:0009046

NotHPOsFreeText:

CaseAddInfo: Symptom onset at 2mo, diagnosis at 4mo, ERT at 5mo, ERT lasted for 67mo, ventilation required at 62mo, currently 6yo

CasePMIDs: 14695532, 14972326

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.1064T>C (p.Leu355Pro)

ClinVar: 284093, https://www.ncbi.nlm.nih.gov/clinvar/variation/284093/

gnomAD: 8.304e-06, http://exac.broadinstitute.org/variant/17-78082197-T-C

CaseOPTPD-5: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.27 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.1222A>G (p.Met408Val)

ClinVar: 371235 https://www.ncbi.nlm.nih.gov/clinvar/variation/371235/

gnomAD: European (Non-Finnish) 1.790e-5, Overall 8.058e-6 http://gnomad.broadinstitute.org/variant/17-78082523-A-G

CaseAddInfo: One Pompe Mutation allele and Two Pseudodeficency Mutation alleles, Nomenclature indicates patient is homozygous for Variant 1 and Variant 2 is in cis with one copy

CaseLP2-12: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.43 umol/hr/L, Serum CK at 29 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1935C>A (p.Asp645Glu)

ClinVar: 4029 https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: East Asian 1.729e-3, Overall 1.240e-4 http://gnomad.broadinstitute.org/variant/17-78086721-C-A

Variant2: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant3: NM_000152.4:c.2482-5T>C

ClinVar: 558320 https://www.ncbi.nlm.nih.gov/clinvar/variation/558320/

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease, Nomenclature indicates Variants 1 and 2 are in cis one one allele and Variants 2 and 3 are in cis on the other

CaseOPOPD-52: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.05 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.1843G>A (p.Gly615Arg)

ClinVar: 188786 https://www.ncbi.nlm.nih.gov/clinvar/variation/188786/

gnomAD: East Asian 2.223e-4, Overall 1.640e-5 http://gnomad.broadinstitute.org/variant/17-78086465-G-A

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 1 other patient has the same genotype

CaseOPOPD-45: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.46 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1411_1414delGAGA (p.Glu471Profs)

ClinVar: 188874 https://www.ncbi.nlm.nih.gov/clinvar/variation/188874/

gnomAD: East Asian 2.513e-4, Overall 1.781e-5 http://gnomad.broadinstitute.org/variant/17-78083827-CGAGA-C

Variant2: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 1 other has the same genotype

CaseOPOPD-4: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.16 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.460_465del (p.Arg154_Thr155del)

ClinVar: 551306 https://www.ncbi.nlm.nih.gov/clinvar/variation/551306/

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

CaseAddInfo: One Pompe Mutation and One Pseudodeficency Mutation

Case59

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.1441T>C (p.Trp481Arg)

ClinVar: 189007 https://www.ncbi.nlm.nih.gov/clinvar/variation/189007/

gnomAD: African 8.031e-5, Overall 2.126e-5 http://gnomad.broadinstitute.org/variant/17-78084529-T-C

Variant2: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://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

CaseAddInfo: Adult Late Onset Pompe Disease

Case90

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.925G>A (p.Gly309Arg)

ClinVar: 188797 https://www.ncbi.nlm.nih.gov/clinvar/variation/188797/

gnomAD: Ashkenazi Jewish 1.010e-4, Overall 2.860e-5 http://gnomad.broadinstitute.org/variant/17-78081665-G-A

Variant2: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://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

CaseAddInfo: Adult Late Onset Pompe Disease, 1 other patient has the same genotype

Case69

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2238G>A (p.Trp746*)

ClinVar: 370904 https://www.ncbi.nlm.nih.gov/clinvar/variation/370904/

gnomAD: African 4.011e-5, Overall 1.063e-5 http://gnomad.broadinstitute.org/variant/17-78090815-G-A

Variant2: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://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

CaseAddInfo: Adult Late Onset Pompe Disease, 1 other patient has the same genotype

Case35

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2238G>A (p.Trp746*)

ClinVar: 370904 https://www.ncbi.nlm.nih.gov/clinvar/variation/370904/

gnomAD: African 4.011e-5, Overall 1.063e-5 http://gnomad.broadinstitute.org/variant/17-78090815-G-A

Variant2: NM_000152.4:c.1843G>A (p.Gly615Arg)

ClinVar: 188786 https://www.ncbi.nlm.nih.gov/clinvar/variation/188786/

gnomAD: East Asian 2.223e-4, Overall 1.640e-5 http://gnomad.broadinstitute.org/variant/17-78086465-G-A

CaseAddInfo: Infantile Onset Pompe Disease

Case38

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2481+102_2646+31del (p.Gly828_Asn882del) (exon 18 del)

ClinVar: 4031 https://www.ncbi.nlm.nih.gov/clinvar/variation/4031/

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.1912G>T (p.Gly638Trp)

CAID: 280954 https://www.ncbi.nlm.nih.gov/clinvar/variation/280954/

gnomAD: African 6.752e-5, Overall 1.239e-5 http://gnomad.broadinstitute.org/variant/17-78086698-G-T

CaseAddInfo: Infantile Onset Pompe Disease

Case24

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2560C>T (p.Arg854*)

ClinVar: 4034 https://www.ncbi.nlm.nih.gov/clinvar/variation/4034/

gnomAD: African 1.891e-3, Overall 2.090e-4 http://gnomad.broadinstitute.org/variant/17-78092070-C-T

Variant2: NM_000152.4:c.2459_2461delCTG (p.Ala820del)

ClinVar: 456404 https://www.ncbi.nlm.nih.gov/clinvar/variation/456404/

gnomAD: European (Non-Finnish) 6.492e-5, Overall 3.190e-5 http://gnomad.broadinstitute.org/variant/17-78091524-GGCT-G

CaseAddInfo: Infantile Onset Pompe Disease

Patient30: Female, 1 year onset

CasePresentingHPOs: HP:0001324, HP:0001263 (Muscle weakness, Developmental delay)

HPOsFreeText: GAA activity 3% from leukocyte

CaseNotHPOs: HP:0002098, HP:0002240, HP:0001640 (Respiratory distress, Hepatomegaly, Cardiomegaly)

NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

CaseAddInfo: LOPD

Patient19: Male, 21 years report, 14 year onset

CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)

HPOsFreeText: GAA activity 9.3% from leukocyte, Respiratory Assistance needed

CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: Wheelchair not needed

CaseAddInfo: LOPD

Patient14: Male, 59 years report, 40 year onset

CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)

HPOsFreeText: GAA activity 6.9% from dried blood spot, Respiratory Assistance needed

CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: Wheelchair not needed

CaseAddInfo: LOPD

Patient20: Male, 22 years report, 12 year onset

CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)

HPOsFreeText: GAA activity 11.6% from leukocyte, Respiratory Assistance needed

CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: Wheelchair not needed

CaseAddInfo: LOPD

Case#: 1, age 36, age 30 (report)

DiseaseAssertion: Pompe Disease

FamilyInfo: Family 1, no further information

CasePresenting HPOs:HP:0002878, HP:0012378, HP:0003546, HP:0001324 (Respiratory failure, fatigue, exercise intolerance, muscle weakness)

CaseHPOFreeText: myopathy with vacuoles, biopsy with vacuolar myopathy with PAS +

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: single gene sequencing/analysis, 48.47 NaG/AaGIA, 89.61% inhibition of GAA; NaG/AaGIA above 40 and %INH above 87 are in the affected range

Variants:

Variant 1:NM_000152.5(GAA):c.1941C>G (p.Cys647Trp)

ClinVar: 550327

Variant 2: Not reported

ParentalGenotypes: N/A

PreviouslyPublished: N/A

Patient1: 7yo

CasePresentingHPOs: HP:0001638

HPOsFreeText: rhGAA dosage = 20QW, independent walker

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 17days old at ERT start

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.784G>A (p.Glu262Lys)

ClinVar: 188806, https://www.ncbi.nlm.nih.gov/clinvar/variation/188806/

gnomAD: 1.66e-05, http://exac.broadinstitute.org/variant/17-78081447-G-A

Patient2: Female, 37yo

CasePresentingHPOs: HP:0003077, HP:0001513

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 10yr disease duration, ERT lasted for 33mo

CasePMIDs: PMID: 25614309

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1655T>C (p.Leu552Pro)

ClinVar: 279811, https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.1478C>T (p.Pro493Leu)

ClinVar: 379593, https://www.ncbi.nlm.nih.gov/clinvar/variation/379593/

gnomAD: 0.00001416, http://gnomad.broadinstitute.org/variant/17-78084566-C-T

Case7: Female, 3 years onset, 3 years diagnosis, 27 years report, France

CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation)

HPOsFreeText: Lost ambulation at 11 years, Started invasive ventilation at 11 years, Started ERT given every other week at a dose of 20 mg/kg at 18 years for 114 months, Peak Anti-rhGAA antibodies at 1:102,400, FVC at 0.22/6 (L / % expected), MIP at 10 (cm H2O), MEP at 10 (cm H2O), Time off ventilation stayed constant at 0 min, Total Motor Function Measure from 23 to 19, 6MWT stayed constant at 0 meters

CaseNotHPOs: HP:0030148 (Heart murmur)

NotHPOsFreeText: No adverse reaction to ERT was recorded

CaseAddInfo: Late Onset Pompe Disease

Patient25: Male, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: c.971dupC (p.Ser325GlufsX5) no ClinVar or CAID

Variant2: NM_000152.4(GAA):c.1802C>T (p.Ser601Leu)

ClinVar: 194154, https://www.ncbi.nlm.nih.gov/clinvar/variation/194154/

gnomAD: n/a

Patient10: Male, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.2105G>A (p.Arg702His)

ClinVar: 426278, https://www.ncbi.nlm.nih.gov/clinvar/variation/426278/

gnomAD: 6.695e-05, http://exac.broadinstitute.org/variant/17-78087081-G-A

Variant2: NM_000152.4(GAA):c.2297A>C (p.Tyr766Ser)

ClinVar: 420102, https://www.ncbi.nlm.nih.gov/clinvar/variation/420102/

gnomAD: 8.35e-06, http://exac.broadinstitute.org/variant/17-78090874-A-C

Case: Female, 59yo, Japanese, non-consanguineous family

CasePresentingHPOs: HP:0002515, HP:0001290, HP:0009055, HP:0002015, HP:0002098, HP:0002315, HP:0007340, HP:0004944, HP:0002138, HP:0001297, HP:0000822, HP:0001288, HP:0002788, HP:0003236, HP:0002119, HP:0002415, HP:0012444, HP:0001922, HP:0012529

HPOsFreeText: 3mm aneurysm in left middle cerebral artery, underwent cerebral arterial clipping, muscle atrophy more significant in proximal muscles of lower limbs, hypotonia more significant in right thigh, CPK = 327mg/dL, alanine aminotransferase = 44mg/dL, aspartate aminotransferase = 42mg/dL, lactic dehydrogenase = 266mg/dL, low-density lipoprotein = 162mg/dL, flattened diaphragm, left atrial ventricular enlargement with mass = 156g, left ventricular index = 106g/m^2, extensor muscle atrophy, diffuse fibrosis in thighs, multiple infractions, bilateral tortuous irregular cerebral arteries, GAA activity = 1.3 pmol hour^-1 punch^-1, vacuolated platelets, glycogen accumulation, large lysosomes filled with membrane bound deposition in fibroblasts

CaseNotHPOs: HP:0003691, HP:0012195, HP:0030850, HP:0010535, HP:0000365, HP:0000505, HP:0002111

NotHPOsFreeText: regurgitation

CaseAddInfo: Hypertension developed at 40yo and was treated with antihypertensive drugs. Cerebral stroke at 57yo. Father died at 82yo due to cardiac aneurism and arterial thrombosis. Mother had left ventricular hypertrophy and died at 62yo due to colon carcinoma. Sister had psychiatric illness. Her 2 sons were healthy.

CasePreviousTesting: CT scan, chest x-ray, echocardiogram, MRI, DBS, electron microscopy of blood cells, skin biopsy

CaseGenotypingMethod: PCR and direct DNA sequencing of GAA gene, cDNA-sequencing analysis

Variant: NM_000152.4(GAA):c.546G>T (p.Thr182=), homozygous

ClinVar: 370637, https://www.ncbi.nlm.nih.gov/clinvar/variation/370637/

gnomAD: n/a

PatientF3P1: Female, 3 months diagnosis, Multiracial (maternal European and Native American and paternal Czechoslovakian, German, and Australian)

CasePresentingHPOs: HP:0004755, HP:0001290 (Supraventricular tachycardia, Generalized hypotonia)

CaseAddInfo: Proband

Patient4: 19yo

CasePresentingHPOs:

HPOsFreeText: hyperCKemia, GAA = 24%, BMI = 26.1, normal CTA and CT

CaseNotHPOs:

NotHPOsFreeText: No cardiovascular risk

CaseAddInfo: 12yr disease duration

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.1771C>T (p.Arg591Trp)

ClinVar: 551782, https://www.ncbi.nlm.nih.gov/clinvar/variation/551782/

gnomAD: 8.662e-06, http://exac.broadinstitute.org/variant/17-78086393-C-T

CasePD/Pathogenic-9: 3 weeks diagnosis

HPOsFreeText: GAA activity 8.4 (nmol · h−1 · mg−1), Mean percentage of normal 11.7%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2065G>A (p.Glu689Lys)

ClinVar: 4030 https://www.ncbi.nlm.nih.gov/clinvar/variation/4030/

gnomAD: East Asian 0.2355, Overall 0.05524 http://gnomad.broadinstitute.org/variant/17-78087041-G-A

Variant3: NM_000152.4:c.2662G>T (p.Glu888Ter)

ClinVar: 578595 https://www.ncbi.nlm.nih.gov/clinvar/variation/578595/

gnomAD: East Asian 2.719e-4, Overall 1.998e-5 http://gnomad.broadinstitute.org/variant/17-78092467-G-T

CaseAddInfo: Patient has one pseudodeficency allele and one pathogenic allele, Nomenclature claims Variant 1 and 2 are in cis

CaseLOPD-16: 2.5 weeks diagnosis

HPOsFreeText: GAA activity 2.5 (nmol · h−1 · mg−1), Mean percentage of normal 3.6%

GenotypingMethod: Newborn Screening Panels

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.2065G>A (p.Glu689Lys)

ClinVar: 4030 https://www.ncbi.nlm.nih.gov/clinvar/variation/4030/

gnomAD: East Asian 0.2355, Overall 0.05524 http://gnomad.broadinstitute.org/variant/17-78087041-G-A

Multiple interpretations of p.W746C possible, below is considered the most likely

Variant3: NM_000152.4:c.2238G>C (p.Trp746Cys)

ClinVar: 265160 https://www.ncbi.nlm.nih.gov/clinvar/variation/265160/

gnomAD: European (Non-Finnish) 5.673e-4, Overall 3.083e-4 http://gnomad.broadinstitute.org/variant/17-78090815-G-C

CaseAddInfo: Late Onset Pompe Disease, Nomenclature claims Variant 2 and 3 are in cis

Case10HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 0.2 pmol/punch/hr, GAA activity at 33% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 https://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1548G>A (p.Trp516Ter)

ClinVar: 189025 https://www.ncbi.nlm.nih.gov/clinvar/variation/189025/

gnomAD: European (Non-Finnish) 1.552e-5, Overall 7.079e-6 https://gnomad.broadinstitute.org/variant/17-78084636-G-A

CaseAddInfo: Patient is compound heterozygous for this variant

Case3: Female, 18 years onset, 19 years diagnosis, 26 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236, HP:0002747 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK, Respiratory muscle weakness)

CaseAddInfo: Late-Onset Pompe Disease

Case6: Female, 22 years onset, 23 years diagnosis, 37 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236, HP:0002747 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK, Respiratory muscle weakness)

CaseAddInfo: Late-Onset Pompe Disease

Patient25: Female

CasePresentingHPOs: HP:0004887

HPOsFreeText: CRIM positive, Anti-rh GGA antibodies maximum titer = ≤ 1:400, tracheostomy, able to sit independently

CaseNotHPOs: HP:0025156, HP:0002546, HP:0000365

NotHPOsFreeText: infusion associated reaction

CaseAddInfo: variants in trans, symptom onset at 2yo, diagnosis at 3yo, ERT at 4yo

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.784G>A (p.Glu262Lys)

ClinVar: 188806, https://www.ncbi.nlm.nih.gov/clinvar/variation/188806/

gnomAD: 0.00001417, http://gnomad.broadinstitute.org/variant/17-78081447-G-A

Patient7: Male, 4.5mo at diagnosis and ERT

CasePresentingHPOs:

HPOsFreeText: classic IOPD, moderate response to ERT, Pompe muscle pathology score = 3.5, Glycogen = 31.4 Vv(PAS + /mf)%, larger empty vacuoles = 38.1 Vv (LEV/mf)%, Autophagic vacuoles = 0,06 %/mf

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous, biopsy taken from  musculus vastus lateralis

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.5(GAA):c.2078dup(p.Ala694Glyfs)

ClinVar: 180143, https://www.ncbi.nlm.nih.gov/clinvar/variation/180143/

gnomAD: n/a

CaseVI,2: Adult onset, 61 years diagnosis

CasePresentingHPOs: HP:0003701, HP:0002795, HP:0003388, HP:0003236, HP:0003198 (Proximal muscle weakness, Abnormal respiration, Easy fatiguability, Increased serum CK, Myopathy)

HPOsFreeText: GAA activity from dried blood spot: 0.22%, Forced Vital Capacity Seated: 2040 (46%), 6-Minute Walking Test: 418 min, Plasma CK 2.5-5x Normal

CaseAddInfo: Late-Onset Pompe Disease

Family 6 - Patients 6a and 6b

FamilyPresentingHPOs: HP:0007340, HP:0003701, HP:0000467, HP:0003327, HP:0200136, HP:0003691, HP:0003306, HP:0002650, HP:0040081, HP:0002111, HP:0100284

HPOsFreeText: myopathic muscle unit action potentials, 6a muscle pathology with vacuolar myopathy with glycogen excess

FamilyNotHPOs: HP:0010628

Ethnicity: Iranian

ProbandLabel: 6a, male, 12yo at onset, 25yo at diagnosis

FamilyAddInfo: 6b (male) dx at 33yo, 6a MRC sum score = 78, 6b MRC sum score = 79, both patients required use of NIV

FamilyPreviousTesting: Respiratory Evaluation: 6a FVC = 19%, 6b FVC = 38%, 6a CK = 820 U/L, 6b CK = 503 U/L, muscle pathology (examined only in 6a), DBS enzyme activity (with inhibition) for 6a = 0 μmol/L/h, for 6b = 0.21 μmol/L/h, NCS, EMG

FamilyGenotypingMethod: GAA analyzed with Sanger Sequencing for entire coding region and conserved exon-intron splice junctions, PCR performed for deletion screening

Variant: NM_000152.4(GAA):c.1979G>A (p.Arg660His)

ClinVar: 189172, https://www.ncbi.nlm.nih.gov/clinvar/variation/189172/

gnomAD: 3.279e-05, http://exac.broadinstitute.org/variant/17-78086765-G-A

Case7: Female, 37 years onset, 38 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 40, GAA Activity at ~4.5 pmol/min/mg before ERT and ~5.5 after

GroupGenotypingMethod: PCR Amplification and GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://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.2237G>A (p.Trp746Ter)

ClinVar: 280063 https://www.ncbi.nlm.nih.gov/clinvar/variation/280063/

gnomAD: European (Non-Finnish) 8.834e-6, Overall 3.988e-6 http://gnomad.broadinstitute.org/variant/17-78090814-G-A

CaseAddInfo: Late Onset Pompe Disease

Case#: Patient 16, female

CasePresentingHPOs: HP:0003325

CaseAddInfo: onset and diagnosis at 32yo

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

VariantAllele2: NC_000017.11:g.(?80118193)(80118357_?)del

ClinVar: 456368, https://www.ncbi.nlm.nih.gov/clinvar/variation/456368/

gnomAD: n/a

Patient11: Female, 39yo at diagnosis, 53yo at ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:400, enzyme (μmol/g/h) = 0.41 (3-20), NIV required only after ERT began, mobility aid required before and after ERT

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 21yr disease duration, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1548G>A (p.Trp516Ter)

ClinVar: 189025, https://www.ncbi.nlm.nih.gov/clinvar/variation/189025/

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.2799+4A>G

ClinVar: 286228, https://www.ncbi.nlm.nih.gov/clinvar/variation/286228/

gnomAD: 8.319e-06, http://exac.broadinstitute.org/variant/17-78092608-A-G

Patient7: female, Serbian

CasePresentingHPOs: HP:0003677, HP:0003236, HP:0003325

HPOsFreeText: CK < 10x increase

CaseNotHPOs: HP:0002093

CaseAddInfo: onset in middle age

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant 1: NM_000152.4(GAA):c.2269C>T (p.Gln757Ter)

ClinVar: 429727, https://www.ncbi.nlm.nih.gov/clinvar/variation/429727/

gnomAD: n/a

Variant2: 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

PatientID: IV-1

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This patient (IV-1) appears to have inherited this disease from his father, along with many of his siblings. See Fig. 1 for family pedigree.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: This member had pheochromocytoma which was not further described.

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: Although never given at the time of this publication, the germline mutation is confirmed in this family in later publications (PMID 7987306; 29437867) for this specific family. It is only here assumed this member had the VHL mutation.

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

PatientID: IV-27

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This patient (IV-27) appears to have inherited this disease from her father. See Fig. 1 for family pedigree.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: This member was examined in St. Johns at the Memorial University of Newfoundland. She had cerebellar hemangioblastoma which were not further described. She also presented with Vitamin-D-Resistant rickets, likely inherited from her father, and non-VHL affected grandmother.

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: Although never given at the time of this publication, the germline mutation is confirmed in this family in later publications (PMID 7987306; 29437867) for this specific family. It is only here assumed this member had the VHL mutation.

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

PatientID: II:9

KindredID: 1

Case: M, Age Unknown, Jewish

DiseaseAssertion: VHL

FamilyInfo: This kindred of Jewish-Kurdish origin consisted of 3 generations of 25 members. 7 were clinically affected subjects with pheochromocytoma (5 of which had the confirmed mutation - I:1, II:2, II:4, II:7 and II:9, as the other 2, II:5 and II:10 were said to have passed due to complications of the disease - prior to any genetic testing), and 4 others were carriers, or pre-symptomatic (III:1, III:3, III:7 and III:12). Subject 11:7 developed a cerebellar hemangioblastoma 25 yr after his initial diagnosis of pheochromocytoma, leading to the clinical diagnosis of VHL in the kindred.

CasePresentingHPOs: HP:0002666; HP:0002668 (pheochromocytoma, paraganglioma)

CaseHPOFreeText: patient had bilateral pheochromocytoma, and extra-adrenal chromafin tumors (abdominal paraganglioma). He also had malignant disease with local recurrence

CaseNotHPOs: HP:0005584 (renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 33471715

SupplementalData: N/A

Variant: p.V166F (c.496G>T)

LegacyVariant: p.V166F (c.709G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/

CAID: N/A

VariantEvidence: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V166F (c.496G>T)

MultipleGeneVariants: N/A

PatientID: I:1

KindredID: 1

Case: F, Age Unknown, Jewish

DiseaseAssertion: VHL

FamilyInfo: This kindred of Jewish-Kurdish origin consisted of 3 generations of 25 members. 7 were clinically affected subjects with pheochromocytoma (5 of which had the confirmed mutation - I:1, II:2, II:4, II:7 and II:9, as the other 2, II:5 and II:10 were said to have passed due to complications of the disease - prior to any genetic testing), and 4 others were carriers, or pre-symptomatic (III:1, III:3, III:7 and III:12). Subject 11:7 developed a cerebellar hemangioblastoma 25 yr after his initial diagnosis of pheochromocytoma, leading to the clinical diagnosis of VHL in the kindred.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: patient had bilateral pheochromocytoma

CaseNotHPOs: HP:0005584 (renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 33471715

SupplementalData: N/A

Variant: p.V166F (c.496G>T)

LegacyVariant: p.V166F (c.709G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/

CAID: N/A

VariantEvidence: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V166F (c.496G>T)

MultipleGeneVariants: N/A

216 patients with clinically expected VHL disease due to family history or presence of VHL typical tumours were routinely examined in an eye centre in Germany between January 2019 and January 2020, majority of which were of European descent (~95%). Since data on the genotype–phenotype correlation of the onset of Retinal Hemangioblastoma (RH) is scarce in relation to VHL disease, this study wanted to inversitage the relationship between VHL gene variants (truncating vs single amino acid substitutions) and the ocular phenotype of the disease. 42 different rare VHL gene variants in 148 patients were detected - some of whom had RH and some who did not. Although date of onset of RH, as well as data on central nervous system haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renal cell carcinoma (ccRCC) and pancreatic neuroendocrine neoplasm (PNEN) were collected, it was not reported on a per patient basis and therefore could not be discussed per variant. Out of the 72 patients with a p.Y98H (c.292T>C) mutation, 57% (41/72) of individuals had RH while the other 43% (31/72) did not. No family information was provided.

GroupID: 10

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

CohortInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

CasePresentingHPOs: N/A

CaseHPOFreeText: This individual patient did NOT have retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

Variant: p.F136Lfs*23 (c.408delT)

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: 43601 https://www.ncbi.nlm.nih.gov/clinvar/variation/43601/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: F136LFS*23 (c.408del)

MultipleGeneVariants: N/A

PatientID: 5

KindredID: 5

Case: M, 43Y0M, 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:0010797; HP:0005562 (Hemangioblastoma, Multiple renal cysts)

CaseHPOFreeText: Multiple or bilateral CNS hemangioblastoma and renal cysts. Diagnosed with VHL Type 1. Phenotypes revised from previous reports (see “PreviouslyPublished” section below for PMID).

CaseNotHPOs: HP:0002666; HP:0009711; HP:0005584 (Pheochromocytoma, Retinal capillary hemangioma, Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19270817 and/or 19949673

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

PatientID: 31

KindredID: 31

Case: F, 42Y0M, 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:0010797; HP:0005584 (Hemangioblastoma, Renal cell carcinoma)

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 (Pheochromocytoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L128P (c.383T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 1208816, https://www.ncbi.nlm.nih.gov/clinvar/variation/1208816/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L128P (c.383T>C)

MultipleGeneVariants: N/A

Between 1994 and 2001, the Dutch VHL working group conducted DNA analysis on 146 probands with VHL-associated manifestations. DNA of probands was extracted from peripheral blood samples. Exons 1, 2 and 3 of the VHL gene and their flanking untranslated and intronic coding sequences were amplified by PCR and subjected to semi-automated sequence analysis. Screening for structural rearrangements, including deletions, involving the VHL gene was performed by Southern blot analysis and the multiplex ligation-dependent probe amplification (MLPA) assay. Deletions encompassing the entire VHL gene were confirmed by FISH analysis on lymphocytes from affected individuals. VHL mutations were identified in 43 families. This mutation (c.509T>A) was detected in 14 VHL patients (family no. 18). Six had retinal hemangioblastoma, 9 had CNS hemangioblastoma, 7 had renal cell carcinoma, 8 had renal cysts, 4 had pheochromocytoma, 5 had pancreatic cysts, 2 had endolymphatic sac tumors, 1 with adnexal papillary tumor of probably mesonephric origin, and 5 had hepatic cysts.

PatientID: V-6

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

Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). The mutation F136C (c.407T>G) was detected in the patient, referred to in the paper by c.620T>G due to a difference in transcript sequence. This missense mutation was found in the VHL gene and one patient with pheochromocytoma.

Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). The Q195* (c.583C>T) mutation was detected in the patient, referred to in the paper by c.796C>T due to a difference in transcript sequence. This nonsense mutation was found in the VHL gene and one patient with pheochromocytoma. This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1).

PatientID: N/A

KindredID: 10

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Nonsyndromic pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F119L (c.357C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.F119L (c.570C>G)

ClinVarID: 625240 https://www.ncbi.nlm.nih.gov/clinvar/variation/625240/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: F119L (c.357C>G)

MultipleGeneVariants: N/A

GroupID: 4578

DiseaseAssertion: VHL

GroupSize: 8

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This group is a family of eight people with the same mutation.

GroupPresentingHPOs: HP:0002666; HP:0005584; HP:0010797; HP:0009711 (Pheochromocytoma, Renal cell carcinoma, Hemangioblastoma, Retinal capillary hemangioma)

GroupHPOFreeText: 4/8 family members had a pheochromocytoma, 7/8 had renal cell carcinoma, 5/8 had hemangioblastoma of the CNS, and 3/8 had retinal angioma. 2/8 family members were described to have cysts but the type or location was not specified.

GroupNotHPOs: HP:0030405 (pancreatic endocrine tumour)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: c.446A>G

ClinVarID: 93326, https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as 446, A to G (Asp to Ser), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.233A>G, p.Asn78Ser (NM_000551.3). Error on author's part regarding protein change.

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

GroupID: 4577

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: 2/3 members with pheochromocytoma, 1/3 members with CNS hemangioblastoma, 1/3 members with retinal angioma and 1/3 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.F119L (c.357C>G)

LegacyVariant: c.570C>G

CaseProblemVariantFreeText: N/A

ClinVarID: 625240, https://www.ncbi.nlm.nih.gov/clinvar/variation/625240/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as 570, C to G (Phe to Leu), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.357C>G, p.Phe119Leu (NM_000551.3).

MutationType: missense_variant;transversion

CivicName: F119L (c.357C>G)

MultipleGeneVariants: N/A

540 patients from 187 unrelated Chinese VHL families at the Peking University First Hospital were all screened for VHL clinical features and germline mutations. Of these, clinical characteristics were observed in 258 patients from 80 unrelated Chinese families. These were reported in this study, grouped by the 21 mutations found. PCR and MLPA on peripheral blood detected the VHL mutations. Possessing the p.R113* (c.337C>T) mutation, 6 members total from 2 families were described, and phenotypic information was given for this group. With ages ranging from 17-66Y, hemangioblastomas were observed in 3/6 members, retinal capillary hemangioma in 3, renal cell carcinoma in 3, pancreatic cysts in 2, and in a papillary cystadenoma of the epididymis genital system tumor (epididymis or broad ligament) 1 member. See more information as this cohort has been previously published in PMID 29330336

540 patients from 187 unrelated Chinese VHL families at the Peking University First Hospital were all screened for VHL clinical features and germline mutations. Of these, clinical characteristics were observed in 258 patients from 80 unrelated Chinese families. These were reported in this study, grouped by the 21 mutations found. PCR and MLPA on peripheral blood detected the VHL mutations. Possessing the p.S65L (c.194C>T) mutation, 24 members total from an unknown number of families were described, and phenotypic information was given for this group. With ages ranging from 15-65Y, hemangioblastomas were observed in 15/24 members, retinal capillary hemangioma in 2, renal cell carcinoma in 9, pancreatic cysts in 11, pheochromocytoma in 1, and a genital system tumor (epididymis or broad ligament) in 4 members. This cohort has been previously published in PMID 29330336; 28388566.

540 patients from 187 unrelated Chinese VHL families at the Peking University First Hospital were all screened for VHL clinical features and germline mutations. Of these, clinical characteristics were observed in 258 patients from 80 unrelated Chinese families. These were reported in this study, grouped by the 21 mutations found. PCR and MLPA on peripheral blood detected the VHL mutations. Possessing the p.P86L (c.257C>T) mutation, 3 families with 4 members total were described, and phenotypic information was given for this group. With ages ranging from 30.3Y +/- 8.0Y, hemangioblastoma was observed in 3/4 members, retinal capillary hemangioma in 2, renal cell carcinoma in 3, pancreatic cysts in 3, and  a genital system tumor (epididymis or broad ligament) in 1 member. Ssee more information as this cohort has been previously published in PMID 29330336 (as 2 families of 3 people total), and 28388566 (as family #20, 21).

540 patients from 187 unrelated Chinese VHL families at the Peking University First Hospital were all screened for VHL clinical features and germline mutations. Of these, clinical characteristics were observed in 258 patients from 80 unrelated Chinese families. These were reported in this study, grouped by the 21 mutations found. PCR and MLPA on peripheral blood detected the VHL mutations. Possessing the p.P86S (c.256C>T) mutation, 3 families with 9 members total were described, and phenotypic information was given for this group. With ages ranging from 35.0Y +/- 15.8Y, hemangioblastoma in 3/9 members, retinal capillary hemangioma in 2, renal cell carcinoma in 5, pancreatic cysts in 3, and pheochromocytoma in 1 member was found. See more information as this cohort has been previously published in PMID 29330336 (3 families with 7 members total), and 28388566 (family #18 and #19).

PatientID: IV-8

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The proband (V-5), his mother (IV-8), maternal grandmother (III-6), maternal aunts (IV-10, IV-12), cousin (V-9) and brother (V-6) were found to harbour the VHL mutation p.P86A (c.256 C>G). All were symptomatic of VHL except for his cousin.

CasePresentingHPOs: HP:0010797; HP:0000107; HP:0030405; HP:0009711 (Hemangioblastoma, Renal cyst, Pancreatic endocrine tumor, Retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7728151(family 4416); 20375333

SupplementalData: Information obtained from Figure 1.

Variant: p.P86A (c.256 C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93327, https://www.ncbi.nlm.nih.gov/clinvar/variation/93327/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: P86A (c.256C>G)

MultipleGeneVariants: N/A

PatientID: CII2

KindredID: C

Case: M, 63Y0M, Serbian

DiseaseAssertion: VHL

FamilyInfo: Families were selected based on their clinical data and family history. Patient’s son (CIII1) retinal capillary hemangioma, CNS hemangioblastoma and renal cell carcinoma, but was not genetically tested. The patient’s brother also had retinal capillary hemangioma, CNS hemangioblastoma and renal cell carcinoma, but was not genetically tested. Patient’s grandson (CIV2) was diagnosed with retinal hemangioblastoma at 12Y0M. Then, multiple pancreatic and kidney cysts were detected at 29Y0M and left kidney cancer was found at age 35Y0M. He possessed the same mutation as the patient. The grandson’s children aged 12Y0M (CV2) and 15Y0M (CV1) are carriers of the same genetic mutation, but are both currently asymptomatic. See pedigree in figure 1.

CasePresentingHPOs: HP:0009711; HP:0010797; HP:0005584 (retinal capillary hemangioma; hemangioblastoma; renal cell carcinoma)

CaseHPOFreeText: The patient had the first symptoms of retinal hemangioblastoma at 60Y0M and deceased due to renal cell carcinoma in both kidneys at 63Y0M.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W88R (c.262T>A)

LegacyVariant: p.W88R (c.475T>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 456577, https://www.ncbi.nlm.nih.gov/clinvar/variation/456577/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense variant; transversion

CivicName: W88R (c.262T>A)

MultipleGeneVariants: N/A

PatientID: CV1

KindredID: C

Case: M, 15Y0M, Serbian

DiseaseAssertion: Asymptomatic

FamilyInfo: Families were selected based on their clinical data and family history. Patient and his brother (CV2) are both currently asymptomatic, but possess the same variant as their father (CIV2), who was diagnosed with retinal hemangioblastoma at 12Y0M. Then, multiple pancreatic and kidney cysts were detected at 29Y0M and left kidney cancer was found at age 35Y0M. Patient’s grandfather, great grandfather and great uncle (CIII1; CII1, CII2) had retinal capillary hemangioma, CNS hemangioblastoma and renal cell carcinoma. Out of the three of them, only the great grandfather had genetic testing performed and was found to have the same mutation as the patient. See pedigree in figure 1.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W88R (c.262T>A)

LegacyVariant: p.W88R (c.475T>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 456577, https://www.ncbi.nlm.nih.gov/clinvar/variation/456577/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense variant; transversion

CivicName: W88R (c.262T>A)

MultipleGeneVariants: N/A

The VHL gene was analyzed in 3 families from a Serbain population. Genomic DNA was screened by SSCP analysis and patients with variant bands were subjected to sequencing and confirmatory re-sequencing. 3 male members (BI1; BII2; BIII3) from Family B had pheochromocytoma. Two of them (BII2; BIII3) were genetically tested and confirmed to possess the missense V84M (c.250G>A) VHL mutation, reported in the paper as V84M (c.463G>A) due to a difference in transcript sequence. Patient BII2 and BIII3 were diagnosed at 40Y and 1Y with pheochromocytoma, respectively.

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. This mutation was found in family #23 with 4 members genetically confirmed for the mutation and 7 affected members. The male proband (patient 60) was diagnosed with CNS hemangioblastoma at 25Y, retinal angioma at 25Y, renal cell carcinoma at 30Y, multiple pancreatic cysts or tumours at 30Y (mutation confirmed); son of unknown age (patient 61) with no manifestations (mutation confirmed); daughter of unknown age (patient 62) with no manifestations (mutation confirmed); father (patient 63) diagnosed with CNS hemangioblastoma at 35Y and retinal angioma at 35Y (passed away before diagnosis/ before mutation confirmed); Sister (patient 64) diagnosed with CNS hemangioblastoma at 24Y, and multiple pancreatic cysts or tumours at 31Y (passed away before diagnosis/ before mutation confirmed); aunt 1 (patient 65) diagnosed with CNS hemangioblastoma at 35Y; aunt 2 (patient 66) diagnosed with CNS hemangioblastoma at 20Y (passed away before diagnosis/ before mutation confirmed); aunt 3 diagnosed with CNS hemangioblastoma at 44Y (passed away before diagnosis/ before mutation confirmed); son of aunt 3 (patient 67) diagnosed with CNS hemangioblastoma at 26Y (mutation confirmed).This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336).

PatientID: 53

KindredID: 18

Case: F, 11Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 51) has a father (patient 52) who passed away before he could be diagnosed/ genetically confirmed with this mutation. The father had renal cell carcinoma at 52. The proband's daughter (patient 53) was confirmed with the mutation and had retinal angioma at 11.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at 31, and renal cell carcinoma and multiple pancreatic cysts/tumors at 32.

CaseNotHPOs: HP:0001737; HP:0001732; HP:0005584; HP:0010797; HP:0002666 (Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma, Hemangioblastoma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient 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.P86S (c.256C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 178692; https://www.ncbi.nlm.nih.gov/clinvar/variation/178692/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P86S (c.256C>T)

MultipleGeneVariants: N/A

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. A male patient (family #16, patient #45) was confirmed with this missense mutation (p.R82P(c.245G>C)) in the VHL gene. He was diagnosed with CNS hemangioblastoma at 40Y and multiple pancreatic cysts or tumours at 26Y. This patient was also published in a paper by Wang et al., 2018 (PMID: 29330336).

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. This familial mutation was confirmed in kindred #63. A female proband (patient 163) was diagnosed with a CNS hemangioblastoma at 37Y, renal cell carcinoma at 37Y, pheochromocytoma at 17Y, and multiple pancreatic lesions at 37Y. Her brother (patient 164) was diagnosed with CNS hemangioblastoma at 27Y, retinal angioma at 26Y, and pheochromocytoma at 8Y. Her niece of unknown age is asymptomatic. Her mother, who was not genetically confirmed with the mutation due to lack of DNA sample, was diagnosed with multiple pancreatic cysts/tumors at 56Y and pheochromocytoma at 56Y. This kindred was also published in a paper by Wang et al., 2018 (PMID: 29330336).

PatientID: 8

KindredID: 8

Case: Sex Unknown, 31Y0M, Italian

DiseaseAssertion: pheochromocytoma

FamilyInfo: Present - potential pathogenic relevance due to a family history, although no further information present

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: adrenal bilateral pheochromocytoma with an age of diagnosis of 31Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G93C (c.277G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223175 https://www.ncbi.nlm.nih.gov/clinvar/variation/223175/

CAID: N/A

gnomAD: 0.000004476 https://gnomad.broadinstitute.org/variant/3-10183808-G-T

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: G93C (c.277G>T)

MultipleGeneVariants: N/A

One hundred and sixteen unrelated VHL disease patients have been investigated by molecular genetic analysis. Twenty-two of these were previously shown to have germline deletions on Southern analysis, and in the present study the remaining 94 patients were screened for intragenic mutations via SSCP and heteroduplex analysis of 855 bp of the VHL coding sequence and 800 bp of the 3' UTR. An intragenic mutation was identified in 55 (59%) out of 94 patients without germline deletions on Southern analysis. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This study also investigated the frequency of different mutation classes between kindreds with and without pheochromocytoma. The p.N78H(c.232A>C) missense mutation (noted as p.N149H (c.445A>C) in the paper due to a difference in reference transcript used) was found in at least one patient in kindred 34. Pheochromocytoma was not observed in any members of this kindred (implying the affected patient(s) had VHL disease type 1). No other familial phenotypic information could be inferred from the paper.

One hundred and sixteen unrelated VHL disease patients have been investigated by molecular genetic analysis. Twenty-two of these were previously shown to have germline deletions on Southern analysis, and in the present study the remaining 94 patients were screened for intragenic mutations via SSCP and heteroduplex analysis of 855 bp of the VHL coding sequence and 800 bp of the 3' UTR. An intragenic mutation was identified in 55 (59%) out of 94 patients without germline deletions on Southern analysis. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This study also investigated the frequency of different mutation classes between kindreds with and without pheochromocytoma. The p.E94 (c.280G>T) missense mutation (noted as p.E165 (c.493G>T) in the paper due to a difference in reference transcript used) was found in at least one patient in kindred 51. Pheochromocytoma was not observed in any members of this kindred (implying the affected patient(s) had VHL disease type 1). No other familial phenotypic information could be inferred from the paper.

One hundred and sixteen unrelated VHL disease patients have been investigated by molecular genetic analysis. Twenty-two of these were previously shown to have germline deletions on Southern analysis, and in the present study the remaining 94 patients were screened for intragenic mutations via SSCP and heteroduplex analysis of 855 bp of the VHL coding sequence and 800 bp of the 3' UTR. An intragenic mutation was identified in 55 (59%) out of 94 patients without germline deletions on Southern analysis. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This study also investigated the frequency of different mutation classes between kindreds with and without pheochromocytoma. The p.Q195 (c.583C>T) stop-gain mutation (noted as c.796C>T (p.Q266) in the paper due to a difference in reference transcript used) was found in at least one patient in kindred no.21. Pheochromocytoma was not observed in any members of this kindred (implying the affected patient(s) had VHL disease type 1). No other familial phenotypic information could be inferred from the paper. ACMG evidence codes: none.

PatientID: 1

KindredID: 1

Case: F, 66Y0M, Taiwanese (East-Asian)

DiseaseAssertion: renal cell carcinoma

FamilyInfo: N/A

CohortInfo: 8 of 19 patients presenting with clear cell renal cell carcinoma were found to be heterozygous for the germline variant rs1642742 in VHL (c.*294G>A). All but one of these patients (7/8) also presented with the germline variant rs779805 (c.-195G>A) in VHL.

CasePresentingHPOs: HP:0006770 (clear cell renal cell carcinoma)

CaseHPOFreeText: She had stage III clear cell renal cell carcinoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 21982469

SupplementalData: Yes - Additional file 1: Figure S1

Variant: c.*294G>A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 342407 https://www.ncbi.nlm.nih.gov/clinvar/variation/342407/

CAID: N/A

gnomAD: 0.5911 https://gnomad.broadinstitute.org/variant/3-10191943-G-A

VariantEvidence: Heterozygous for both, she also presented with the germline variant c.-195G>A in VHL. LOH (G) of both mutations was found in the tumor tissue as well

MutationType: 3_prime_UTR_variant

CivicName: c.-195G>A AND c.*294G>A

MultipleGeneVariants: Germline, VHL, c.-195G>A

In a robotic adrenalectomy case report, a 13-year-old male pediatric case was noted with intermittent tachycardic and hypertensiveity during hospitalization for a pneumonia episode. He found to have a 6cm right adrenal mass. It was resected and he remains disease-free at 19 months of post-operative follow-up. Patient’s father has VHL, and had undergone bilateral adrenalectomy for pheochromocytoma and bilateral nephrectomy for renal cell carcinoma. A VHL mutation (c.583C>T, p.Q195*) was found in the patient and his father. No information was mentioned regarding genotyping method or sampling method.

A 6Y old boy presented at the Children's Hospital with left adrenal pheochromocytoma, and relapsed with right adrenal pheochromocytoma a year later. His outcome was uneventful in a five year follow-up. His father had left adrenal pheochromocytoma and left extra-adrenal paraganglioma when the father was 11Y, and had an uneventful outcome. A germline VHL missense transversion mutation NM_000551.3:c.488T>G(L163R) was confirmed in both the son and father, and was found by sequencing with polymerase chain reaction (PCR) and analysis with single-strand conformation polymorphism (SSCP). The patient's mother and 3 other siblings had no symptoms and no mutation. Note that the paper describes this variant as c.701T>G since it uses an older reference sequence (Latif et al.).

Fourty-four of 389 patients with VHL (between 1988-1999) screened positive for PNETs either by pathologic analysis of tissue specimens or by characteristic radiographic appearance on CT and MRI. VHL gene germline mutations were determined by quantitative Southern blotting to detect deletions of the gene and gene rearrangements as well as complete gene sequencing. Patient 16, a 24-year-old female, was found to harbour the c.555C>G mutation in the VHL gene (stated as 768 C to G in the paper which used the Latif sequence as reference) leading to a premature stop codon at protein position 185 in exon 3. She presented with a single pathologic pancreatic neuroendocrine tumor. ACMG evidence codes: 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

PatientID: None

KindredID: 32165

Case: Age unknown, Sex unknown, Turkish

DiseaseAssertion: VHL

FamilyInfo: familial Turkish germline mutation

CasePresentingHPOs: HP:0010797; HP:0002666 (hemangioblastoma, pheochromocytoma)

CaseHPOFreeText: Bilateral pheochromocytoma and CNS hemangioblastoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes

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

This study reports 1,548 germline and somatic mutations from 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). This mutation (p.P86S (c.256C>T)) was detected by direct sequencing and MLPA in 2 VHL kindreds. One family had pheochromocytoma, renal cell carcinoma, and retinal angiomas (case no. 182). The other family had hemangioblastomas of the central nervous system (case no. 177). ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease, 'PP4' because the patient's phenotypes or family history are highly specific for a disease with single genetic etiology.

A Mexican family with Von Hippel-Lindau disease was identified. The family consisted of 6 clinically affected members, 3 of which received genetic testing that demonstrated the presence of the R82P (c.245G>C) germline mutation of the VHL gene. Genomic DNA was extracted from peripheral blood leukocytes and the entire VHL coding sequence was amplified using PCR and direct automated sequencing of VHL was performed. Genetic testing was also performed in 21 clinically asymptomatic family members. 3 of these individuals were found to carry the same mutation, but it was concluded they were too young to manifest the disease. Clinical manifestations present in this family include: cerebellar hemangioblastoma, retinal hemangioblastoma, renal cell carcinoma, and pheochromocytoma. Beyond this, one of the asymptomatic carriers of this variant presented with atrophy of the retinal pigment epithelium at age 4.

PatientID: III-3

KindredID: 1

Case: M, 32Y0M, Mexican

DiseaseAssertion: VHL

FamilyInfo: Family composed of six affected individuals and three diseased subjects (III-2, III-3, III-4) were studied. III-4 (proband) presented with a CNS hemangioblastoma and a retinal hemangioblastoma. The mother (II-1) developed cerebellar, medullar and bilateral retinal HBs; two maternal aunts (II-2 and II-3) were affected by retinal and CNS HBs and unspecified renal tumors, whereas his grandfather (I-2) had unspecified abdominal tumors. All these relatives died in their early 30s. A 35-year-old sister (III-2) demonstrated cerebellar HB, right eye retinal HB and renal cell carcinoma, whereas a 32-year-old brother (III-3) presented with cerebellar HB, right eye retinal HB, renal cell carcinoma and pheochromocytoma. A mutation-carrier nephew (IV-2) presented only atrophy of the retinal pigment epithelium. All of these family members were found to have the R82P (c.245G>C) germline VHL variant. Eighteen additional healthy relatives were analyzed and tested negative for the mutation.

CohortInfo: Two families and one apparently non-familial case were studied at the Institute of Ophthalmology ‘Conde de Valenciana’ (Mexico City, Mexico).

CasePresentingHPOs: HP:0006880; HP:0009711; HP:0005584; HP:0002666 (Cerebellar hemangioblastoma, Retinal capillary hemangioma, Renal cell carcinoma, Pheochromocytoma)

CaseHPOFreeText: Cerebellar HB, right eye retinal HB, renal cell carcinoma and pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Family pedigree (Figure 1 (a))

Variant: p.R82P (c.245G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 526675, https://www.ncbi.nlm.nih.gov/clinvar/variation/526675/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R82P (c.245G>C)

MultipleGeneVariants: N/A

Molecular and clinical analysis of 126 French VHL families tested for renal involvement revealed 92 different mutations. 90 of these families had renal involvement. The p.L188P (c.563T>C) germline variant of the VHL gene was detected in 2 individuals (ID 5730/Family 269 and ID 8828/Family 1005) who both presented with renal cell carcinoma. The paper states that these families are previously reported in PMID 12202531 and/or 9829912.

Molecular and clinical analysis of 126 French VHL families tested for renal involvement revealed 92 different mutations. 90 of these families had renal involvement. The p.R161Q (c.482G>A) germline variant of the VHL gene was detected in a family (ID 60). Member 1603 presented with mild renal disease. Member 1601 presented with severe renal disease (RCC). An individual from another family (ID 6270, Family 279) was also found with this variant and presented with renal cell carcinoma. The paper states that these families are previously reported in PMID 12202531 and/or 9829912.

PatientID: 3404

KindredID: 209

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 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.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). Individual RCC phenotype is noted as positive.

CaseNotHPOs: N/A

CaseHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 9829912

SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

Variant: p.S65L (c.194C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182975, https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65L (c.194C>T)

MultipleGeneVariants: N/A

Molecular and clinical analysis of 126 French VHL families tested for renal involvement revealed 92 different mutations. 90 of these families had renal involvement. The p.L158P (c.473T>C) germline variant of the VHL gene was detected in an individual (ID 5342, Family 252). They presented with renal cell carcinoma. The paper states that this individual is previously reported in PMID 12202531 and/or 9829912.

GroupID: 60

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 members of this family were found to harbor the c.482G>A germline variant of the VHL gene. Member 1603 presented with mild renal disease. Member 1601 presented with severe 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:0009726; HP:0005584 (Renal neoplasm, Renal cell carcinoma)

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]). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

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 3 individuals and 3 families 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. These previously published individuals could alternatively correspond to family 279.

SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

Variant: p.R161Q (c.482G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 63F

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 Neuro Olcologie database in Paris, with an unknown number of members belonging to Family ID 63F. 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.Y175* (c.525C>G)

LegacyVariant: p.Y175* (c.738C>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 182974 https://www.ncbi.nlm.nih.gov/clinvar/variation/182974

CAID: N/A

gnomAD: N/A

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

MutationType: stop_gained

CivicName: Y175* (c.525C>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: 3616NCI

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 National Cancer Institute database, with an unknown number of members belonging to Family ID 3616NCI. 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.V155Cfs*4 (c.462delA)

LegacyVariant: FS (c.675delA)

CaseProblemVariantFreeText: N/A

ClinVarID: 625251 https://www.ncbi.nlm.nih.gov/clinvar/variation/625251/

CAID: N/A

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

MutationType: minus_1_frameshift_variant

CivicName: V155fs (c.462delA)

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 (N78S (c.233A>G)) was taken from multiple databases including: the Department of Uroglogy, Yokohama database, the Munich, university of Freiburg and Institute of Pathology database, the National Cancer Institute database, and the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family IDs 9YO, 51CE, 4327NCI, 160CA. It was reported in the paper as c.446A>G 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: 46YO, 19CA, 27F

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 multiple databases including: the Department of Uroglogy, Yokohama database, the Cambridge, Department of Pathology database, and the Neuro Olcologie database in Paris, with an unknown number of members belonging to Family IDs 46YO, 19CA, 27F. 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.L118P (c.353T>C)

LegacyVariant: p.L118P (c.566T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 428807 https://www.ncbi.nlm.nih.gov/clinvar/variation/428807/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L118P (c.353T>C)

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 (V170D (c.509T>A)) was taken from the Utrecht, The Netherlands database and the Cambridge, Department of Pathology database. It had an unknown number of members belonging to Family ID R-D, reported in Table 4, as being found in VHL families with pheochromocytoma. Additionally, it was reported in table 5, specified as families without detailed clinical information, under family ID 77CA. It was reported in the paper as c.722T>A due to a difference in transcript reference.

GroupID/ KindredID: 49CA

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 49CA. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Described as a VHL family with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P154L (c.461C>T)

LegacyVariant: p.P154L (c.674C>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 649525 https://www.ncbi.nlm.nih.gov/clinvar/variation/649525/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P154L (c.461C>T)

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 (W117C (c.351G>T)) was taken from the Neuro Olcologie database in Paris and the National Cancer Institute databases, with an unknown number of members belonging to Family IDs 13F, 564NCI, 1239NCI. It was reported in the paper as c.564G>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. Later publications reference this cohort as being reported in PMIDs: 7728151 and 9829911.

GroupID/ KindredID: 98CA

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 98CA. 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.Q96P (c.287A>C)

LegacyVariant: p.Q96P (c.500A>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 625233 https://www.ncbi.nlm.nih.gov/clinvar/variation/625233/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: Q96P (c.287A>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 9YO, 51CE, 4327NCI, 160CA

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 Department of Uroglogy, Yokohama database, the Munich, university of Freiburg and Institute of Pathology database, the National Cancer Institute database, and the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 9YO, 51CE, 4327NCI, 160CA. 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.N78S (c.233A>G)

LegacyVariant: p.N78S (c.446A>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

PatientID: Proband

KindredID: 1

Case: M, 32Y0M, ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Family history showed that his mother had unilateral vision loss (multiple retinal hemangioblastomas in both eyes) and died because of renal cell carcinoma. No mutation was detected. His sister and daughter were found to have the p.R161* variant. No pathology was detected in ophthalmologic examination of the patient’s 12-year-old daughter.

CasePresentingHPOs: HP:0009711; HP:0000572; HP:0010797; HP:0000107 (retinal capillary hemangioma; vision loss; hemangioblastoma; renal cyst)

CaseHPOFreeText: presented with vision loss in the left eye for 2 months - had a history of cerebral hemangioblastoma operation. Patient also underwent surgery approximately 8 years earlier (24Y) due to a cranial mass (cerebral hemangioblastoma). Cortical cyst 13 mm in diameter was detected in the left kidney on renal ultrasonography (USG).

CaseNotHPOs: N/A

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: VHL gene sequence analysis revealed a heterozygous mutation.

MutationType: stop_gained

CivicName: R161* (c.481C>T)

MultipleGeneVariants: N/A vh

41 non-related patients with retinal capillary hemangioma presenting in the Benjamin Franklin University Eye Clinic between 1988 to 1999 Germany were evaluated for the presence of other VHL lesions. VHL disease was diagnosed in 33 patients based on the presence of other severe VHL lesions (spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cyst, renal carcinoma, and pheochromocytoma), molecular genetic testing, and/or family history. VHL germline mutations were identified in 27 out of 29 VHL families screened with molecular genetics. Blood samples were genetically tested using PCR-SSCP sequencing. One patient (14Y, female) presented with vision loss due to a single juxtapapillary angioma and was found to have germline nonsense (c.492G>T) mutation in the VHL gene. Her brother (27Y) was also found to have the variant but did not present with any VHL phenotypes. The probands’ sister was negative for the variant. This variant was reported as c.705G>T (AF010238.1) and mapped to p.Q164H (c.492G>T) (NM_000551.3).

41 non-related patients with retinal capillary hemangioma presenting in the Benjamin Franklin University Eye Clinic between 1988 to 1999 Germany were evaluated for the presence of other VHL lesions. VHL disease was diagnosed in 33 patients based on the presence of other severe VHL lesions (spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cyst, renal carcinoma, and pheochromocytoma), molecular genetic testing, and/or family history. VHL germline mutations were identified in 27 out of 29 VHL families screened with molecular genetics. Blood samples were genetically tested using PCR-SSCP sequencing. One patient with VHL-related retinal angiomatosis was found to have germline nonsense (c.280G>T) mutation in the VHL gene. 1 other affected relative was also evaluated and found to have this mutation but no phenotype information was provided. This variant was reported as c.493G>T (AF010238.1) and mapped to p.E94* (c.280G>T) (NM_000551.3). It's unclear which other VHL-related lesions were identified in these patients.

41 non-related patients with retinal capillary hemangioma presenting in the Benjamin Franklin University Eye Clinic between 1988 to 1999 Germany were evaluated for the presence of other VHL lesions. VHL disease was diagnosed in 33 patients based on the presence of other severe VHL lesions (spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cyst, renal carcinoma, and pheochromocytoma), molecular genetic testing, and/or family history. VHL germline mutations were identified in 27 out of 29 VHL families screened with molecular genetics. Blood samples were genetically tested using PCR-SSCP sequencing. One patient with VHL-related retinal angiomatosis was found to have germline missense (c.278G>T) mutation in the VHL gene. This variant was reported as c.491G>T (AF010238.1) and mapped to p.G93V (c.278G>T) (NM_000551.3). It's unclear which other VHL-related lesions were identified in this patient.

PatientID: None

KindredID: 31

Case: Age, sex ethnicity unknown

DiseaseAssertion: unknown; paper focused only on pheochromocytoma

FamilyInfo: No specific family info was present; although this was recorded as a family germline mutation belonging to Family ID 31. Mutation detected by DNA sequencing.

CasePresentingHPOs: N/A

CaseHPOFreeText: Unknown or unstated.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: No presence of phaeochromocytoma in family

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161* (c.481C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: R161* (c.694C>T)

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

PatientID: N/A (father)

KindredID: 1

Case: M, 33Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Analyses of his daughter revealed this mutation after adrenal pheochromocytoma were discovered before she was 3Y. Genetic testing was done on this patient, his wife, his other child, and his parents. The mutation was found to have occurred de novo as both of his parents were negative.

CasePresentingHPOs: HP:0009711; HP:0000107; HP:0030424; HP:0006748 (retinal capillary hemangioma, hemangioblastoma, endolymphatic sac tumor, adrenal pheochromocytoma)

CaseHPOFreeText: After testing of his daughter, this man, free of medical complaints, was screened to find a retinal angioma, an adenoma of the right adrenal gland of 1.5 cm in diameter, a right-sided renal cyst, an epididymal cyst, a contrast-enhancing lesion in the pancreas and bilateral pheochromocytomas with pronounced tracer-uptake on I-123-MIBG-scan and F-18-DOPA-PET-scan were detected. Noradrenaline, normetanephrine, and plasma-normetanephrine were elevated. Chromogranin A values were increased in plasma. The father underwent laparoscopic bilateral adrenalectomy and received focal ophthalmologic treatment for the retinal angioma. 

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q164R (c.491A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2238 https://www.ncbi.nlm.nih.gov/clinvar/variation/2238/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Q164R (c.491A>G)

MultipleGeneVariants: N/A