Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.

The VHL gene product (pVHL) has two macromolecular sites, α and β domains, which can bind different proteins. pVHL bound to elongin B, C/cullin/Rbx1 acts as an E3 ubiquitin ligase and targets proteins for degradation.22 Similarly, hypoxia inducible proteins are regulated by complex pVHL/elongin B and C that requires direct binding of hypoxia inducible factor (HIF) to the β domain and targets HIF for ubiquitination catalysed by the α domain.23 The VHL protein also plays a role in extracellular matrix formation and is necessary for cell cycle exit.24,25 Germline VHL mutations cause different protein defects that result in the clinical heterogeneity of VHL disease. VHL type 1 disease (without phaeochromocytoma) is associated with mutations predicted to cause complete unravelling of protein structure (missense mutations mapping to VHL protein hydrophobic core, protein truncating mutations, and partial gene deletions). VHL type 2 (with phaeochromocytoma) is caused by missense mutations which map to protein binding sites of pVHL and are predicted to cause local protein defects.22 Specific phaeochromocytoma associated missense mutations confer different risks of HAB and RCC, being responsible for the occurrence of subcategories VHL type 2A (VHL without RCC), 2B (VHL with RCC), and 2C (phaeochromocytoma only).15 Phenotypic expression of VHL disease is also influenced by genetic modifiers.26