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 (E55fs (c.163delG)) was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 3682NCI. It was reported in the paper as c.376delG due to a difference in transcript reference. Additionally, this family ID is stated again in Table 3 under the mutation c.439T>A. Unclear if this is a typo, or if multiple mutations belong to this one family. As reported in Table 3, this mutation is found in VHL family without pheochromocytoma, and with renal cell carcinoma. Later publications reference this cohort as being reported in PMID: 7728151.

GroupID/ KindredID: 3682NCI

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 3682NCI. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma. Additionally, this family ID is stated again in Table 3 under the mutation c.226T>A. Unclear if this is a typo, or if multiple mutations belong to this one family.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

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

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 7728151

SupplementalData: N/A

Variant: p.E55Rfs*12 (c.163delG)

LegacyVariant: (c.376delG)

CaseProblemVariantFreeText: N/A

ClinVarID: 428800 https://www.ncbi.nlm.nih.gov/clinvar/variation/428800/

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: E55fs (c.163delG)

MultipleGeneVariants: N/A

PCR amplification was performed searching for point mutation in the entire VHL coding sequence and promoter region, including exon-intron boundaries. Amplification was performed in a Gene Amp PCR System 9700 (Perkin Elmer). When mutations were detected in DNA from tumor samples, it was searched for in the corresponding peripheral blood DNA in order to identify germline mutations. For case 3, table 2 described no mutations found through analysis of HB and peripheral blood. Case 3 was thus said to have sporadic, non-familial disease - however, her sister at 53Y had a single cerebellar hemangioblastoma, with 1 germline and 2 somatic point mutations. These are described further in PMID: 24335534 as P25L(c.74C>T) [germline], D126Rfs*6(c.375_376insA) [somatic], and E55Rfs(c.163delG) [somatic]. It is unclear as to whether the germline mutation was confirmed in case 3.