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.Y185 (c.555C>G) variant (noted as p.Y256 (c.768C>G) in the paper due to a difference in reference transcript used) was found in at least one patient in kindreds 82 and 88. Pheochromocytoma was not observed in any members of either kindred (implying the affected patient(s) had VHL disease type 1). No other familial phenotypic information could be inferred from the paper.

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangoblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. Southern blot and/or MLPA analysis by whole blood detected this mutation (c.555C>G) was found in 3 VHL families with 4 patients altogether. All four had retinal hemangioblastomas and cerebellar hemangioblastomas. Two had renal cell carcinoma.

GroupID: 36

DiseaseAssertion: assumed VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 4 of the 573 patients discussed in this paper were found to have the following mutation belonging to 3 families altogether.

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

GroupHPOFreeText: all 4 patients had retinal angiomas diagnosed at a mean age of 30Y and cerebellar hemangioblastomas diagnosed with a mean age of 25Y, and 2 had RCC diagnosed at a mean age of 29Y

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.Y185* (c.555C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223233 https://www.ncbi.nlm.nih.gov/clinvar/variation/223233/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Y185* (c.555C>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: 88CA, 82CA

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 the Cambridge, Department of Pathology database. There was an unknown number of members belonging to Family IDs: 88CA and 82CA. 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.Y185* (c.555C>G)

LegacyVariant: p.Y185* (c.768C>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 223233 https://www.ncbi.nlm.nih.gov/clinvar/variation/223233/

CAID: N/A

gnomAD: N/A

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

MutationType: stop_gained

CivicName: Y185* (c.555C>G)

MultipleGeneVariants: N/A