Genotype and phenotype correlation in von Hippel-Lindau disease based on alteration of the HIF-α binding site in VHL protein

Genet Med. 2018 Oct;20(10):1266-1273. doi: 10.1038/gim.2017.261. Epub 2018 Mar 29.


Purpose: Von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome that reduces life expectancy. We aimed to construct a more valuable genotype-phenotype correlation based on alterations in VHL protein (pVHL).

Methods: VHL patients (n = 339) were recruited and grouped based on mutation types: HIF-α binding site missense (HM) mutations, non-HIF-α binding site missense (nHM) mutations, and truncating (TR) mutations. Age-related risks of VHL-associated tumors and patient survival were compared.

Results: Missense mutations conferred an increased risk of pheochromocytoma (HR = 1.854, p = 0.047) compared with truncating mutations. The risk of pheochromocytoma was lower in the HM group than in the nHM group (HR = 0.298, p = 0.003) but was similar between HM and TR groups (HR = 0.901, p = 0.810). Patients in the nHM group had a higher risk of pheochromocytoma (HR = 3.447, p < 0.001) and lower risks of central nervous system hemangioblastoma (CHB) (HR = 0.700, p = 0.045), renal cell carcinoma (HR = 0.610, p = 0.024), and pancreatic tumor (HR = 0.382, p < 0.001) than those in the combined HM and TR (HMTR) group. Moreover, nHM mutations were independently associated with better overall survival (HR = 0.345, p = 0.005) and CHB-specific survival (HR = 0.129, p = 0.005) than HMTR mutations.

Conclusion: The modified genotype-phenotype correlation links VHL gene mutation, substrate binding site, and phenotypic diversity (penetrance and survival), and provides more accurate information for genetic counseling and pathogenesis studies.

Keywords: genotype–phenotype; protein binding site; survival; tumor risk; von Hippel–Lindau disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Binding Sites / genetics
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / pathology
  • Female
  • Genetic Association Studies
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Male
  • Middle Aged
  • Mutation, Missense / genetics
  • Protein Binding
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics*
  • von Hippel-Lindau Disease / genetics*
  • von Hippel-Lindau Disease / pathology


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human