GroupID/ KindredID: 4

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: N/A

GroupInfo: With a family history, 3 family members were recorded in this group with the given mutation.

GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0001732 (hemangioblastoma; retinal capillary hemangioma; pancreatic lesion)

GroupHPOFreeText: 2 members had CNS hemangioblastomas, 1 member had retinal angiomas, and 1 had pancreatic cysts or tumors (an abnormality of the pancreas)

GroupNotHPOs: HP:0005584; HP:0002666 (renal cell carcinoma, pheochromocytoma)

GroupNotHPOFreeText: No family members appeared to have the above manifestation.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V74G (c.221T>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.V74G (c.434T>G)

ClinVarID: N/A

CAID: CA70042528 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.221T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V74G (c.221T>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 (V74G (c.221T>G)) was taken from the Munich, university of Freiburg and Institude of Pathology database (reported in Table 3, found in VHL family without pheochromocytoma, and with renal cell carcinoma) with an unknown number of members belonging to Family ID 53CE, as well as Family ID 9CE (reported in Table 4, found in VHL families with pheochromocytoma). It was reported in the paper as c.434T>G due to a difference in transcript reference. Other phenotypes are likely, however not detailed here.

PatientID: 25

KindredID: N/A

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: The authors evaluated 64 VHL patients (32 women and 32 men) with renal involvement of whom 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 VHL patients, at least one or more RCC were diagnosed, however at the time of diagnosis an indication for treatment was not yet present. For all patients several CT/MRI scans existed for retrospective description of tumour growth kinetics.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: This is a tumor resolution study (VHL patients were investigated based on the presence of renal tumors.) No other phenotypic information is available.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1 describes 19 patients with missense mutations, including this patient.

Variant: p.V74G(c.221T>G)

LegacyVariant: c.434T>G

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA70042528

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V74G (c.221T>G)

MultipleGeneVariants: N/A

A cohort of 141 patients with hemangioblastomas of the central nervous system was analyzed. 81 patients had germline mutations in the VHL gene, analyzed through peripheral blood by Southern blotting and SSCP analysis. This missense mutation (c.221T>G) was recorded in the paper as c.434T>G due to a difference in transcript sequence. It was found in 3 patients with hemangioblastomas of the central nervous system, one of which had primary asymptomatic tumors. Any relation between patients is unknown. No other phenotypes described.

Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in 2 unrelated, German families. The mutation of V74G (c.221T>G) was referred to in the paper by c.434T>G due to a difference in transcript sequence. The VHL type 1 family of 4 affected individuals had 2 patients with retinal angiomas, 5 with hemangioblastomas of the central nervous system, and one with renal cyst and noted with a primitive neuroectodermal tumor (family VHL 53). The VHL type 2B family of 3 affected individuals had one patient with retinal angioma, 3 with hemangioblastomas of the central nervous system, one with pheochromocytoma, one with renal cell carcinoma and renal cysts, one with pancreatic cysts, and one with cystadenomas of the epididymis (family VHL 9). This study contains supporting evidence of pathogenicity due to cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1).

GroupID/ KindredID: 53CE

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 Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 53CE. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without phechromocytoma.

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.V74G (c.221T>G)

LegacyVariant: p.V74G (c.434T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA70042528 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.221T>G

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V74G (c.221T>G)

MultipleGeneVariants: N/A