Clinical implications of germline pathogenic variants in the VHL gene

von Hippel-Lindau disease is an inherited multi-organ neoplastic syndrome affecting primarily the retina, central nervous system, kidneys, and neuroendocrine organs. Germline pathogenic sequence variants (PSVs) underlying familial VHL cases are detected in VHL, a tumor suppressor gene that localizes to 3p25.3. The gene product, pVHL, is involved in oxygen sensing and adaptive response to hypoxia, predominantly via HIF and downstream proteins, as well as in HIF-independent pathways. The location of the PSVs along the gene and the specific affected protein domain, as well as the extent of the effects of these PSVs on pVHL function, are tightly associated with the resulting phenotype. Despite the high penetrance rates (over 80%) of germline PSVs, the great phenotypic variability, even among identical PSV carriers, is an obstacle in providing a personalized, targeted, effective early detection scheme. However, the ability to detect VHL PSV carriers in the asymptomatic phase and provide a tight surveillance scheme to facilitate tumor detection at an early, presumably curable stage is partly responsible for the improved life expectancy of VHL cases over the past two decades. Furthermore, a deeper understanding of the molecular basis of VHL may provide more personalized therapeutic and potentially risk-reducing interventions in VHL cases.