Under this hypothesis, the VHL variants identified in our probands would be GoF variants; however, the variants identified in Probands 9, 10, and 11 have been associated with von Hippel-Lindau syndrome, indicating that they are LoF variants that lead to increased HIF-1α and HIF-2α protein levels in tumor tissue in which the wild-type VHL allele is inactivated by deletion, point mutation, or methylation. This evidence concerns the gene EPAS1 and von Hippel-Lindau disease.