Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangoblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This nonsense mutation (c.264G>A) was found in a VHL family with 3 affected members, 1 had retinal hemangioblastomas, 1 had cerebellar hemangioblastomas, 2 had renal cell carcinoma, and 1 had pheochromocytoma. There is very strong evidence for pathogenicity in the form of a nonsense variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1).

Eligible patients were all index cases with clinical diagnosis or clinical suspicion of type 1 VHL referred for genetic testing from 2003 to 2015. Universal primer quantitative fluorescent multiplex polymerase chain reaction (UPQFM-PCR) and multiplex ligation-dependent probe amplification (MLPA) analysis was completed using peripheral blood leukocytes. This patient (ID #22) was found with this VHL nonsense mutation (c.264G>A) when they were 13Y. They did not fulfil type 1 VHL clinical diagnosis. They presented with CNS hemangioblastoma at 13Y. Family history was unremarkable.