ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000003.11) (NC_000003.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
20151405 2010 review of the molecular genetics of the VHL gene, including the mutational spectrum and associated phenotypes. Analysis of 945 VHL families from numerous sources revealed partial and complete VHL deletions account for 11% of all VHL mutations in their cohort.

Haploinsufficiency phenotype comments:

Loss-of-function-type mutations (including whole gene deletions) in the gene VHL are associated with autosomal dominant von Hippel-Lindau syndrome (VHL, OMIM: 193300). VHL is a cancer predisposition syndrome characterized by the development of hemangioblastomas of the brain, spine, and retina, renal lesions (including renal cysts and renal cell carcinoma), pheochromocytoma, paragangliomas, pancreatic lesions (including pancreatic cysts and neuroendocrine tumors), endolymphatic sac tumors, epididymal or papillary cystadenomas, and additional tumor types. The mean age-of-onset for VHL is ~26 years and the penetrance is approximately 87-97% by age 60 (see GeneReviews, OMIM, and PMIDs: 27966541 and 2274658). Of note, homozygous or trans-heterozygous (germline) mutations in VHL are associated with the autosomal recessive condition, Familial Erythrocytosis-2 (OMIM: 263400).

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

There are currently no reported focal duplications of VHL. Therefore the triplosensitivity for this gene is 0. Additional related literature is summarized below: Chabchoub et al., 2010 (PMID: 20420027) reported a small (251 kb) non-focal duplication encompassing VHL and IRAK2 in a 17-year-old male presenting with intellectual disability, multiple congenital anomalies, epilepsy, and ectomorphic habitus. The patient was reported to have no tumors and had no history of familial cancer. This duplication was paternally inherited.