VHL von Hippel-Lindau tumor suppressor [Homo sapiens (human)] - Gene

Summary

Official Symbol: VHLprovided by HGNC
Official Full Name: von Hippel-Lindau tumor suppressorprovided by HGNC
Primary source: HGNC:HGNC:12687
See related: Ensembl:ENSG00000134086 MIM:608537; AllianceGenome:HGNC:12687
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: RCA1; VHL1; pVHL; HRCA1
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]
Expression: Ubiquitous expression in lymph node (RPKM 12.2), spleen (RPKM 10.0) and 25 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 3p25.3

Exon count:: 4

Annotation release	Status	Assembly	Chr	Location
110	current	GRCh38.p14 (GCF_000001405.40)	3	NC_000003.12 (10141778..10153667)
110	current	T2T-CHM13v2.0 (GCF_009914755.1)	3	NC_060927.1 (10134670..10146564)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	3	NC_000003.11 (10183462..10195351)

Chromosome 3 - NC_000003.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Differential VHL Mutation Patterns in Bilateral Clear Cell RCC Distinguishes Between Independent Primary Tumors and Contralateral Metastatic Disease.
Title: Differential VHL Mutation Patterns in Bilateral Clear Cell RCC Distinguishes Between Independent Primary Tumors and Contralateral Metastatic Disease.
Comprehensive characterization of Alu-mediated breakpoints in germline VHL gene deletions and rearrangements in patients from 71 VHL families.
Title: Comprehensive characterization of Alu-mediated breakpoints in germline VHL gene deletions and rearrangements in patients from 71 VHL families.
TET2 Suppresses VHL Deficiency-Driven Clear Cell Renal Cell Carcinoma by Inhibiting HIF Signaling.
Title: TET2 Suppresses VHL Deficiency-Driven Clear Cell Renal Cell Carcinoma by Inhibiting HIF Signaling.
iASPP is essential for HIF-1alpha stabilization to promote angiogenesis and glycolysis via attenuating VHL-mediated protein degradation.
Title: iASPP is essential for HIF-1α stabilization to promote angiogenesis and glycolysis via attenuating VHL-mediated protein degradation.
Whole-Exome Sequencing Identifies the VHL Mutation (c.262T > C, p.Try88Arg) in Non-Obstructive Azoospermia-Associated Cystic Renal Cell Carcinoma.
Title: Whole-Exome Sequencing Identifies the VHL Mutation (c.262T &gt; C, p.Try88Arg) in Non-Obstructive Azoospermia-Associated Cystic Renal Cell Carcinoma.
VHL-P138R and VHL-L163R Novel Variants: Mechanisms of VHL Pathogenicity Involving HIF-Dependent and HIF-Independent Actions.
Title: VHL-P138R and VHL-L163R Novel Variants: Mechanisms of VHL Pathogenicity Involving HIF-Dependent and HIF-Independent Actions.
Multi-Omics Profiling to Assess Signaling Changes upon VHL Restoration and Identify Putative VHL Substrates in Clear Cell Renal Cell Carcinoma Cell Lines.
Title: Multi-Omics Profiling to Assess Signaling Changes upon VHL Restoration and Identify Putative VHL Substrates in Clear Cell Renal Cell Carcinoma Cell Lines.
Investigation of VHL gene associated with miR-223 in clear cell renal cell carcinoma.
Title: Investigation of VHL gene associated with miR-223 in clear cell renal cell carcinoma.
Deubiquitylase OTUD6B stabilizes the mutated pVHL and suppresses cell migration in clear cell renal cell carcinoma.
Title: Deubiquitylase OTUD6B stabilizes the mutated pVHL and suppresses cell migration in clear cell renal cell carcinoma.
rs779805 Von Hippel-Lindau Gene Polymorphism Induced/Related Polycythemia Entity, Clinical Features, Cancer Association, and Familiar Characteristics.
Title: rs779805 Von Hippel-Lindau Gene Polymorphism Induced/Related Polycythemia Entity, Clinical Features, Cancer Association, and Familiar Characteristics.

Submit: New GeneRIF Correction See all GeneRIFs (576)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Professional guidelines

Description
Professional guideline ACMG 2013 The ACMG recommends that laboratories performing clinical sequencing seek and report mutations in VHL that are pathogenic or expected to be pathogenic. GuidelinePubMed

Associated conditions

Description	Tests
Chuvash polycythemia MedGen: C1837915 OMIM: 263400 GeneReviews: Not available	Compare labs
Nonpapillary renal cell carcinoma MedGen: CN074294 OMIM: 144700 GeneReviews: Not available	Compare labs
Pheochromocytoma MedGen: C0031511 OMIM: 171300 GeneReviews: Hereditary Paraganglioma-Pheochromocytoma Syndromes	Compare labs
Von Hippel-Lindau syndrome MedGen: C0019562 OMIM: 193300 GeneReviews: Von Hippel-Lindau Syndrome	Compare labs

Copy number response

Description
Copy number response Triplosensitivity No evidence available (Last evaluated 2022-05-11) ClinGen Genome Curation Page Haploinsufficency Sufficient evidence for dosage pathogenicity (Last evaluated 2022-05-11) ClinGen Genome Curation PagePubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

L17688 (e-PCR)
- UniSTS:74509

GDB:434012 (e-PCR)
- UniSTS:157204

L17705 (e-PCR)
- UniSTS:66091

SHGC-31692 (e-PCR)
- UniSTS:82991

STS-L15409 (e-PCR)
- UniSTS:69168

VHL__5065 (e-PCR)
- UniSTS:463929

GDB:361137 (e-PCR)
- UniSTS:156737

GDB:361141 (e-PCR)
- UniSTS:156738

GDB:361144 (e-PCR)
- UniSTS:156739

GDB:361147 (e-PCR)
- UniSTS:156740

GDB:361151 (e-PCR)
- UniSTS:156741

GDB:375126 (e-PCR)
- UniSTS:157004

RH16642 (e-PCR)
- UniSTS:12631

L18426 (e-PCR)
- UniSTS:34648

SHGC-57727 (e-PCR)
- UniSTS:53086

RH71303 (e-PCR)
- UniSTS:44639

SHGC-33879 (e-PCR)
- UniSTS:69217

RH79802 (e-PCR)
- UniSTS:88688

D15S1477 (e-PCR)
- UniSTS:474482

D1S1423 (e-PCR)
- UniSTS:149619

GDB:532940 (e-PCR)
- UniSTS:157555

GDB:532945 (e-PCR)
- UniSTS:157556

GDB:532951 (e-PCR)
- UniSTS:157557

GDB:532957 (e-PCR)
- UniSTS:157558

GDB:532965 (e-PCR)
- UniSTS:157559

L17971 (e-PCR)
- UniSTS:43966

GDB:270439 (e-PCR)
- UniSTS:156352

GDB:631802 (e-PCR)
- UniSTS:158429

GDB:631813 (e-PCR)
- UniSTS:158430

D5S1597E (e-PCR)
- UniSTS:151019

Homology

Homologs of the VHL gene: The VHL gene is conserved in Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog.
Orthologs from Annotation Pipeline: 401 organisms have orthologs with human gene VHL
Orthologs

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables DNA-binding transcription factor binding	IPI Inferred from Physical Interaction more info	PubMed
enables enzyme binding	IPI Inferred from Physical Interaction more info	PubMed
enables molecular adaptor activity	EXP Inferred from Experiment more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables transcription elongation factor activity	IDA Inferred from Direct Assay more info	PubMed
enables ubiquitin ligase-substrate adaptor activity	IDA Inferred from Direct Assay more info	PubMed
enables ubiquitin-protein transferase activity	TAS Traceable Author Statement more info

Process	Evidence Code	Pubs
involved_in DNA-templated transcription elongation	IEA Inferred from Electronic Annotation more info
involved_in amyloid fibril formation	EXP Inferred from Experiment more info	PubMed
involved_in amyloid fibril formation	IDA Inferred from Direct Assay more info	PubMed
involved_in cell morphogenesis	NAS Non-traceable Author Statement more info	PubMed
involved_in cellular response to hypoxia	TAS Traceable Author Statement more info
involved_in negative regulation of apoptotic process	NAS Non-traceable Author Statement more info	PubMed
involved_in negative regulation of cell population proliferation	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of cell population proliferation	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in negative regulation of gene expression	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in negative regulation of receptor signaling pathway via JAK-STAT	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in negative regulation of signal transduction	EXP Inferred from Experiment more info	PubMed
involved_in negative regulation of transcription elongation by RNA polymerase II	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of transcription from RNA polymerase II promoter in response to hypoxia	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of DNA-templated transcription	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of cell differentiation	NAS Non-traceable Author Statement more info	PubMed
involved_in protein stabilization	NAS Non-traceable Author Statement more info	PubMed
involved_in protein ubiquitination	IDA Inferred from Direct Assay more info	PubMed
involved_in protein ubiquitination	IEA Inferred from Electronic Annotation more info
involved_in protein ubiquitination	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in proteolysis	TAS Traceable Author Statement more info	PubMed
involved_in regulation of DNA-templated transcription	IMP Inferred from Mutant Phenotype more info	PubMed

Component	Evidence Code	Pubs
located_in cytosol	TAS Traceable Author Statement more info
located_in endoplasmic reticulum	NAS Non-traceable Author Statement more info	PubMed
is_active_in intracellular non-membrane-bounded organelle	EXP Inferred from Experiment more info	PubMed
located_in membrane	IEA Inferred from Electronic Annotation more info
located_in mitochondrion	NAS Non-traceable Author Statement more info	PubMed
located_in nucleoplasm	IDA Inferred from Direct Assay more info
located_in nucleoplasm	TAS Traceable Author Statement more info
located_in nucleus	TAS Traceable Author Statement more info	PubMed

General protein information

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Preferred Names: von Hippel-Lindau disease tumor suppressor

Names: elongin binding protein; protein G7; von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_008212.3 RefSeqGene

Range

5001..17036

Download

GenBank, FASTA, Sequence Viewer (Graphics), LRG_322

mRNA and Protein(s)

NM_000551.4 → NP_000542.1 von Hippel-Lindau disease tumor suppressor isoform 1

See identical proteins and their annotated locations for NP_000542.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) encodes the longest isoform (1).

Source sequence(s)

AC034193

Consensus CDS

CCDS2597.1

UniProtKB/Swiss-Prot

P40337, Q6PDA9

UniProtKB/TrEMBL

A0A024R2F2, A0A0S2Z4I2

Related

ENSP00000256474.3, ENST00000256474.3

Conserved Domains (2) summary

cd05468
Location:64 → 203

pVHL; von Hippel-Landau (pVHL) tumor suppressor protein

cl25865
Location:7 → 86

Trypan_PARP; Procyclic acidic repetitive protein (PARP)
NM_001354723.2 → NP_001341652.1 von Hippel-Lindau disease tumor suppressor isoform 3

Status: REVIEWED

Description

Transcript Variant: This variant (3) lacks an alternate in-frame exon and contains another alternate exon compared to variant 1. The resulting isoform (3) has a shorter and distinct C-terminus compared to variant 1.

Source sequence(s)

AC034193

Related

ENSP00000512435.1, ENST00000696143.1

Conserved Domains (2) summary

cl03381
Location:63 → 113

pVHL; von Hippel-Landau (pVHL) tumor suppressor protein

cl25865
Location:7 → 86

Trypan_PARP; Procyclic acidic repetitive protein (PARP)
NM_198156.3 → NP_937799.1 von Hippel-Lindau disease tumor suppressor isoform 2

See identical proteins and their annotated locations for NP_937799.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) lacks an in-frame coding exon compared to variant 1. The resulting isoform (2) lacks an internal region, as compared to isoform 1.

Source sequence(s)

AC034193

Consensus CDS

CCDS2598.1

UniProtKB/Swiss-Prot

P40337

UniProtKB/TrEMBL

A0A0S2Z4K1

Related

ENSP00000344757.2, ENST00000345392.2

Conserved Domains (3) summary

pfam17211
Location:114 → 163

VHL_C; VHL box domain

cl03381
Location:63 → 113

pVHL; von Hippel-Landau (pVHL) tumor suppressor protein

cl25865
Location:7 → 86

Trypan_PARP; Procyclic acidic repetitive protein (PARP)