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 (D126fs (c.375dupC)) was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 102CA. It was reported in the paper as c.588insC 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: 102CA

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 102CA. 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.D126Rfs*6 (c.375_376insC)

LegacyVariant: FS (c.588insC)

CaseProblemVariantFreeText: c.375_376insC automaps to NM_000551.3:c.375dupC

ClinVarID: N/A

CAID: CA16621931 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.375dupC

gnomAD: N/A

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

MutationType: duplication; plus_1_frameshift_variant

CivicName: D126fs (c.375dupC)

MultipleGeneVariants: N/A

In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. The D126Rfs*6 (c.375dup) germline variant of the VHL gene was found in a 24 year old patient (ID 107) presenting with CNS hemangioblastoma and retinal hemangioblastoma. Parents and siblings were negative for the mutation confirming it as de novo in the proband. No phenotype details are noted for these family members. The variant was reported as c.375_376insC and was mapped to c.375dup. This variant also potentially alters the beta domain of the VHL protein.