Mutations in the von Hippel-Lindau (VHL) gene are pathogenic in VHL disease, congenital polycythaemia and clear cell renal carcinoma.
pVHL forms a ternary complex with Elongin C and Elongin B, critical for pVHL stability and function, which interacts with Cullin-2 and
RING-box protein 1 to target Hypoxia-inducible factor for polyubiquitination and proteasomal degradation.
We describe a comprehensive database of missense VHL mutations linked to experimental and clinical data. We use predictions from in silico tools to link the functional effects of missense VHL mutations to phenotype in VHL disease. The risk of clear cell Renal carcinoma in VHL disease is linked to the degree of destabilisation resulting from missense mutations. An optimised binary classification system, called Symphony, which integrates predictions from five in silico methods, can predict the risk of ccRCC associated with VHL missense mutations with high sensitivity and specificity.
Here, we also present the predictive results of a systematic evaluation carried out on all possible mutations in pVHL, which were compiled in a relational database.