• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
VHL (HGNC:12687) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
von Hippel-Lindau tumor suppressor
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
No previous names found
Alias symbols
VHL1
%HI
45.43(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.08(Read more about gnomAD pLI score)
LOEUF
0.93(Read more about gnomAD LOEUF score)
Cytoband
3p25.3
Genomic Coordinates
GRCh37/hg19: chr3:10183462-10195351 NCBI Ensembl UCSC
GRCh38/hg38: chr3:10141778-10153667 NCBI Ensembl UCSC
MANE Select Transcript
NM_000551.4 ENST00000256474.3 (Read more about MANE Select)
Function
Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex (PubMed:10944113, PubMed:17981124, PubMed:19584355). Seems to act as a target recruitment subunit in the E3 ubiquitin ligase complex and recruits hydroxylated hypoxia-inducible factor (HIF) under normoxic conditions (PubMed:10944113, PubMed:17981124). Involved in transcriptional repression through interaction with HIF1A, HIF1AN and histone deacetylases (PubMed:10944113, PubMed:1... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-15992
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
05/11/2022

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 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.
  • PUBMED: 33362845
    Qiu J et al (2020) performed a retrospective study of 577 Chinese VHL patients from 211 families to establish a genotype-phenotype association based on mutation locations. Both mutation types and location was found to be associated with phenotypes. Mutations detected were 52% missense, 13% frameshift, 11% nonsense, 6% in-frame deletions/insertions, 11% large/complete deletions and 7% splice mutations.
HI Evidence 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 (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
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.

Genomic View

Select assembly: (NC_000003.11) (NC_000003.12)