rs104893829

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.

Study of germline VHL gene mutations in 93 von Hippel-Lindau disease families detected mutations in 100% of families (vs. 39-80% in prior studies). Of 78 distinct mutations identified, 8 were complete gene deletions (10%), 23 were partial deletions (30%), and 47 were point mutations (60%). Thirteen novel mutations were reported. Strong genotype-phenotype correlations were confirmed: codon 167 mutations occurred in 46% of VHL type 2 (with pheochromocytoma) vs 3% of VHL type 1 (p=0.000002), and missense mutations were more frequent in type 2 (69%) vs type 1 (27%, p=0.003).