GeneBe

VHL

protein-coding

von Hippel-Lindau tumor suppressor

Gene summary

This gene encodes a component of a ubiquitination complex. The encoded protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. In addition to oxygen-related gene expression, this protein plays a role in many other cellular processes including cilia formation, cytokine signaling, regulation of senescence, and formation of the extracellular matrix. Variants of this gene are associated with von Hippel-Lindau syndrome, pheochromocytoma, erythrocytosis, renal cell carcinoma, and cerebellar hemangioblastoma. [provided by RefSeq, Jun 2022]

MANE transcript

NM_000551.4

Inheritance

AD, AR

ClinVar variants

P:467U:470B:443

Top phenotype

Von Hippel Lindau; Erythrocytosis, familial, 2 (Chuvash polycythemia); Pheochromocytoma

gnomAD constraint

pLI —, LoF o/e 0.36

Max pathogenic AF

—

Genomic locus

chr3:10,141,778-10,153,676

External References & Databases

Ensembl (ENSG00000134086)NCBI Gene (7428)OMIM (608537)HGNC:12687GenCCUniProt (P40337)AlphaFoldClinVar (VHL)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~11.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary pheochromocytoma-paragangliomaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017366

Submitter: Orphanet

von Hippel-Lindau diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008667

Submitter: Orphanet

renal cell carcinomaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0005086

Submitter: Genomics England PanelApp

Chuvash polycythemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009892

Submitter: Orphanet

von Hippel-Lindau diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008667

Submitter: Labcorp Genetics (formerly Invitae)

pheochromocytomaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008233

Submitter: G2P

von Hippel-Lindau diseaseDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008667

Submitter: G2P

Chuvash polycythemiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009892

Submitter: Genomics England PanelApp

von Hippel-Lindau diseaseDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008667

Submitter: ClinGen

The VHL gene is associated with the autosomal dominant cancer syndrome von Hippel Lindau disease which includes retinal hemangiomas, cerebellar and spinal hemangioblastomas, renal cell carcinoma and pheochromocytomas https://www.ncbi.nlm.nih.gov/books/NBK1463/. . Following multiple reports of segregation and linkage analysis from large pedigrees of VHL-affected families (PMID: 6582782, PMID: 2642584, PMID: 1982450, PMID: 1680799), the VHL gene was identified by Latif et al in 1993 (PMID: 8493574). Numerous variants have been reported in VHL in relation to the development of von Hippel Lindau disease, and this gene curation relies on a cohort of 114 cases with 12 unique VHL truncating and missense variants from Chen et al 1995 (PMID:7728151) . Although the present curation does not distinguish between VHL Type 1 and Type 2, generally, truncating and grossly damaging missense are associated with VHL Type 1 while less damaging missense are associated with VHL Type 2. The present curation does not include Chuvash Polycythemia or associated variants. Other databases describing germline VHL variants include: Clinical Interpretations of Variants in Cancer (https://civicdb.org), VHLdb (http://vhldb.bio.unipd.it/home), and large compendiums of genetic variants (PMID: 20151405). There is extensive genetic evidence supporting this gene-disease relationship including both case-level and familial data. The VHL gene is a tumor-suppressor with a wide variety of cellular functions (PMID: 25533676), most notably in regulation of Hypoxia Inducible Factor A (HIFa) through binding to hydroxylated HIFa, which induces subsequent ubiquitination and proteasomal degradation (PMID: 25533676). To bind hydroxylated HIFa, VHL is assembled into a complex with CUL2, RBX1 and Elongin B and C (VCB complex). The molecular mechanism of VHL dysfunction in von Hippel Lindau disease involves mutations which result in absent or reduced assembly of the VCB complex, or absent/reduced binding of the VCB complex (VHL) to HIFa. This gene-disease relationship is supported experimentally by expression studies, biochemical function, functional alterations and animal models. In summary, VHL is definitively associated with the autosomal autosomal dominant von Hippel Lindau syndrome. This has been demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

Chuvash polycythemiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009892

Submitter: Labcorp Genetics (formerly Invitae)

von Hippel-Lindau diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008667

Submitter: Genomics England PanelApp

autosomal recessive secondary polycythemia not associated with VHL geneSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0016598

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Von Hippel Lindau; Erythrocytosis, familial, 2 (Chuvash polycythemia); PheochromocytomaAD/AR

Manifestation: Cardiovascular; Hematologic; Oncologic

Intervention: Cardiovascular; Hematologic; Oncologic

Rationale: In VHL, surveillance for and early treatment of malignant complications (eg, hypertension and hypokalemia resulting from pheochromocytoma, as in isolated Pheochromocytoma) may be beneficial; Individuals with Erythrocytosis, familial, 2 have a high risk for peripheral thrombosis and cerebrovascular events, and preventive measures and early treatment may be beneficial, though the efficacy of interventions such as phlebotomy is questionable

Comments: Depending on the condition, individuals can have primarily oncologic (Von Hippel Lindau) or hematologic (Chuvash polycythemia) manifestations

Refs: 13494077; 14142412; 4453572; 449657; 573913; 431135; 3790978; 2897130; 3200963; 2642584; 2066108; 1673491; 1347089; 1593692; 1436350; 8493574; 7987306; 7977949; 8059782; 8069305; 8592333; 8825918; 8929948; 9329368; 9398721; 9145719; 9058738; 9215674; 9663592; 10408776; 10554035; 10697963; 10830910; 11106358; 11097604; 10631138; 11688380; 11987242; 12415268; 12629069; 12844285; 14500227; 14726398; 15190140; 14695531; 14711727; 15599750; 15642664; 16210343; 17057815; 16518846; 17609489; 17311301; 19464396; 20151405; 20301636; 21606165; 21713522; 21972040; 21993671; 22265326; 22393103; 23781388; 23827964; 23897319; 23968328Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to VHL variants in ClinVar

32 Conditions Cataloged
Von Hippel-Lindau syndromeTotal: 1678
Chuvash polycythemiaTotal: 1474
Hereditary cancer-predisposing syndromeTotal: 886
not providedTotal: 327
PheochromocytomaTotal: 116
Nonpapillary renal cell carcinomaTotal: 103
not specifiedTotal: 102
VHL-related disorderTotal: 63

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000551.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
2
clinvar
5
clinvar
265
clinvar
17
clinvar
 291
missense
80
clinvar
142
clinvar
414
clinvar
143
clinvar
11
clinvar
 790
nonsense
35
clinvar
3
clinvar
18
clinvar
 56
start loss
1
clinvar
1
clinvar
3
clinvar
6
clinvar
 11
frameshift
120
clinvar
29
clinvar
27
clinvar
1
clinvar
 177
splice donor/acceptor (+/-2bp)
42
clinvar
10
clinvar
3
clinvar
 55
Total280187470415281380

Highest pathogenic variant AF is 0.00022552385

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000551.4RefSeqNP_000542.13MANE Select
ENST00000256474.3EnsemblENSP00000256474.33MANE Select
NM_001354723.2RefSeqNP_001341652.12Standard
NM_198156.3RefSeqNP_937799.12Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
vhlDanio rerio

Structure: hematopoietic multipotent progenitor cell

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Renal cell carcinoma - Homo sapiens (human)
  • HIF-1 signaling pathway - Homo sapiens (human)
  • Ubiquitin mediated proteolysis - Homo sapiens (human)
  • Pathways in cancer - Homo sapiens (human)
  • Angiogenesis overview

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • cell morphogenesis
  • regulation of transcription, DNA-templated
  • proteolysis
  • negative regulation of cell population proliferation

Molecular Function

  • ubiquitin-protein transferase activity
  • protein binding
  • transcription factor binding
  • enzyme binding
  • ubiquitin protein ligase activity

Cellular Component

  • nucleus
  • nucleoplasm
  • mitochondrion
  • endoplasmic reticulum
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000256474
Coding exons
3
Length
11213
Individuals with no LoFs
125746
Homozygous LoFs
0
Heterozygous LoFs
2
Defined
125748
p
0.00000795
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.3951361241.100.000006751340
Missense (PolyPhen)4441.9571.0487479
Synonymous-0.6306357.01.110.00000307440
Loss of Function1.7238.360.3594.47e-783

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.00000880.0000088rare
South Asian0.0000650.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Seems to act as a target recruitment subunit in the E3 ubiquitin ligase complex and recruits hydroxylated hypoxia- inducible factor (HIF) under normoxic conditions. Involved in transcriptional repression through interaction with HIF1A, HIF1AN and histone deacetylases. Ubiquitinates, in an oxygen-responsive manner, ADRB2. {ECO:0000269|PubMed:10944113, ECO:0000269|PubMed:17981124, ECO:0000269|PubMed:19584355}.;
Disease
DISEASE: Pheochromocytoma (PCC) [MIM:171300]: A catecholamine- producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. {ECO:0000269|PubMed:12000816, ECO:0000269|PubMed:14500403, ECO:0000269|PubMed:9663592}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: von Hippel-Lindau disease (VHLD) [MIM:193300]: VHLD is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms, most frequently retinal, cerebellar and spinal hemangioblastoma, renal cell carcinoma (RCC), pheochromocytoma, and pancreatic tumors. VHL type 1 is without pheochromocytoma, type 2 is with pheochromocytoma. VHL type 2 is further subdivided into types 2A (pheochromocytoma, retinal angioma, and hemangioblastomas without renal cell carcinoma and pancreatic cyst) and 2B (pheochromocytoma, retinal angioma, and hemangioblastomas with renal cell carcinoma and pancreatic cyst). {ECO:0000269|PubMed:10408776, ECO:0000269|PubMed:10533030, ECO:0000269|PubMed:10627136, ECO:0000269|PubMed:10635329, ECO:0000269|PubMed:16502427, ECO:0000269|PubMed:7728151, ECO:0000269|PubMed:7987306, ECO:0000269|PubMed:8493574, ECO:0000269|PubMed:8592333, ECO:0000269|PubMed:8634692, ECO:0000269|PubMed:8730290, ECO:0000269|PubMed:8825918, ECO:0000269|PubMed:8956040, ECO:0000269|PubMed:9452032, ECO:0000269|PubMed:9452106, ECO:0000269|PubMed:9829911, ECO:0000269|PubMed:9829912, ECO:0000269|Ref.41}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Erythrocytosis, familial, 2 (ECYT2) [MIM:263400]: An autosomal recessive disorder characterized by an increase in serum red blood cell mass, hypersensitivity of erythroid progenitors to erythropoietin, increased erythropoietin serum levels, and normal oxygen affinity. Patients with ECYT2 carry a high risk for peripheral thrombosis and cerebrovascular events. {ECO:0000269|PubMed:12393546, ECO:0000269|PubMed:12844285}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Renal cell carcinoma (RCC) [MIM:144700]: Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma. Clear cell renal cell carcinoma is the most common subtype. {ECO:0000269|PubMed:11986208}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool
0.0364
RVIS EVS
0.06
RVIS percentile EVS
58.26

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
E
Essential (gene trap)
H
Indispensability pred.
E
Indispensability score
0.973

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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