rs104893824

Systematic mutation screening of the VHL tumor suppressor gene in 114 unrelated von Hippel-Lindau disease families identified germline mutations in 75% of families. Sixty-seven different mutations were detected, predominantly clustered in exons 1 and 3. Strikingly, VHL families with pheochromocytoma (VHL type 2) were caused almost exclusively by missense mutations (96%), while VHL type 1 families without pheochromocytoma were predominantly caused by truncating mutations (56% microdeletions, nonsense, and deletions). Codon 238 mutations accounted for 43% of type 2 mutations, and 99% of patients with pheochromocytomas carried missense mutations, suggesting that full-length mutant VHL protein with residual function is required for pheochromocytoma development.

International analysis of 469 von Hippel-Lindau (VHL) disease families identified 300 families (63%) carrying germline mutations, with 137 distinct intragenic mutations detected. Germline VHL mutations produced three distinct cancer phenotypes: renal carcinoma without pheochromocytoma (VHL type 1), renal carcinoma with pheochromocytoma (VHL type 2B), and pheochromocytoma without renal carcinoma (VHL type 2A). Identical germline mutations including delPhe76, Asn78Ser, Arg161Stop, Arg167Gln, Arg167Trp, and Leu178Pro produced consistent cancer phenotypes across Caucasian and Japanese populations.