In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This insertion mutation was detected in a VHL type 1 patient (family ID 4410), using PCR and SSCP sequencing. The mutation of c.386_387insAGA was referred to in the paper by c.599insAGA due to a difference in transcript sequence. The patient had retinal hemangioblastomas, CNS hemangioblastomas, and renal cell carcinoma. Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4).

PatientID: None

KindredID: 4410

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Familial VHL stated; although only 1 family member recorded.

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L129_V130insGlu (c.386_387insAGA)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.200insE (c.599insAGA)

ClinVarID: N/A

CAID: CA16602182 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.386_387insAGA

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_insertion

CivicName: L129Q (c.386insAGA)

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 (L129_V130insE (c.386_387insAGA)) was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 4410NCI. It was reported in the paper as c.599insE 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.