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

Gene ID: 7428, updated on 27-Nov-2024

Summary

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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
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Genomic context

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See VHL in Genome Data Viewer
Location:
3p25.3
Exon count:
4
Annotation release Status Assembly Chr Location
RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 3 NC_000003.12 (10141778..10153667)
RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 3 NC_060927.1 (10134670..10146564)
RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 3 NC_000003.11 (10183462..10195351)

Chromosome 3 - NC_000003.12Genomic Context describing neighboring genes Neighboring gene 3p25 BRK1 Alu-mediated recombination region Neighboring gene small nucleolar RNA U13 Neighboring gene uncharacterized LOC124906359 Neighboring gene 3p25 von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase Alu-mediated recombination region Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:10184379-10184912 Neighboring gene 3p25 IRAK2 Alu-mediated recombination region Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14055 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14056 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chr3:10210671-10211181 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19418 Neighboring gene interleukin 1 receptor associated kinase 2 Neighboring gene H3K27ac hESC enhancer GRCh37_chr3:10227030-10227530 Neighboring gene H3K27ac hESC enhancer GRCh37_chr3:10227531-10228031 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19419 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19420 Neighboring gene Sharpr-MPRA regulatory region 12699 Neighboring gene U6 spliceosomal RNA Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:10266988-10267770 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19421 Neighboring gene Sharpr-MPRA regulatory region 8698 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:10275792-10276394 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14057 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14058 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:10290711-10291579 Neighboring gene 3p25 TatD DNase domain containing 2 Alu-mediated recombination region Neighboring gene TatD DNase domain containing 2 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14059 Neighboring gene microRNA 12127

Genomic regions, transcripts, and products

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Go to nucleotide: Graphics FASTA GenBank

Expression

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  • 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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Related articles in PubMed

  1. Two pediatric patients with Von Hippel-Lindau disease type 2b: from patient to screening, from screening to patient. Gonc N, et al. J Pediatr Endocrinol Metab, 2011. PMID 21528828
  2. Phosphorylation of the von Hippel-Lindau protein (VHL) by protein kinase CK2 reduces its protein stability and affects p53 and HIF-1alpha mediated transcription. Ampofo E, et al. Int J Biochem Cell Biol, 2010 Oct. PMID 20637892
  3. Biomarkers predicting outcome in patients with advanced renal cell carcinoma: Results from sorafenib phase III Treatment Approaches in Renal Cancer Global Evaluation Trial. Peña C, et al. Clin Cancer Res, 2010 Oct 1. PMID 20651059
  4. No evidence for DNA methylation of von Hippel-Lindau ubiquitin ligase complex genes in breast cancer. Huang KT, et al. Breast Cancer Res Treat, 2010 Dec. PMID 20680678
  5. Quantitative image analysis identifies pVHL as a key regulator of microtubule dynamic instability. Thoma CR, et al. J Cell Biol, 2010 Sep 20. PMID 20855504, Free PMC Article

See all (907) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. Clinical implications of activation of the LIMD1-VHL-HIF1alpha pathway during head-&-neck squamous cell carcinoma development.
    Title: Clinical implications of activation of the LIMD1-VHL-HIF1α pathway during head-&-neck squamous cell carcinoma development.
  2. Network modeling links kidney developmental programs and the cancer type-specificity of VHL mutations.
    Title: Network modeling links kidney developmental programs and the cancer type-specificity of VHL mutations.
  3. VHL mutation drives human clear cell renal cell carcinoma progression through PI3K/AKT-dependent cholesteryl ester accumulation.
    Title: VHL mutation drives human clear cell renal cell carcinoma progression through PI3K/AKT-dependent cholesteryl ester accumulation.
  4. Characterization of spinal hemangioblastomas in patients with and without von Hippel-Lindau, and YAP expression.
    Title: Characterization of spinal hemangioblastomas in patients with and without von Hippel-Lindau, and YAP expression.
  5. Induction of the Mdm2 gene and protein by kinase signaling pathways is repressed by the pVHL tumor suppressor.
    Title: Induction of the Mdm2 gene and protein by kinase signaling pathways is repressed by the pVHL tumor suppressor.
  6. VHL suppresses UBE3B-mediated breast tumor growth and metastasis.
    Title: VHL suppresses UBE3B-mediated breast tumor growth and metastasis.
  7. REST-dependent downregulation of von Hippel-Lindau tumor suppressor promotes autophagy in SHH-medulloblastoma.
    Title: REST-dependent downregulation of von Hippel-Lindau tumor suppressor promotes autophagy in SHH-medulloblastoma.
  8. VHL loss reprograms the immune landscape to promote an inflammatory myeloid microenvironment in renal tumorigenesis.
    Title: VHL loss reprograms the immune landscape to promote an inflammatory myeloid microenvironment in renal tumorigenesis.
  9. VHL governs m6A modification and PIK3R3 mRNA stability in clear cell renal cell carcinomas.
    Title: VHL governs m6A modification and PIK3R3 mRNA stability in clear cell renal cell carcinomas.
  10. Von Hippel Lindau tumor suppressor controls m6A-dependent gene expression in renal tumorigenesis.
    Title: Von Hippel Lindau tumor suppressor controls m6A-dependent gene expression in renal tumorigenesis.
Submit: New GeneRIF Correction See all GeneRIFs (598)

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)

Pathways from PubChem

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Interactions

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Products Interactant Other Gene Complex Source Pubs Description

General gene information

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Markers

Homology

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-like 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 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 TORC1 signaling IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in negative regulation of apoptotic process NAS
Non-traceable Author Statement
more info
 PubMed 
involved_in negative regulation of autophagy IDA
Inferred from Direct Assay
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 by RNA polymerase II IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in negative regulation of transcription elongation by RNA polymerase II 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 proteasome-mediated ubiquitin-dependent protein catabolic process IDA
Inferred from Direct Assay
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 
involved_in regulation of cellular response to hypoxia EXP
Inferred from Experiment
more info
 PubMed 
involved_in regulation of gene expression EXP
Inferred from Experiment
more info
 PubMed 
involved_in regulation of gene expression IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in regulation of gene expression IEP
Inferred from Expression Pattern
more info
 PubMed 
Component Evidence Code Pubs
located_in cytosol TAS
Traceable Author Statement
more info
  
is_active_in endoplasmic reticulum IDA
Inferred from Direct Assay
more info
 PubMed 
located_in endoplasmic reticulum NAS
Non-traceable Author Statement
more info
 PubMed 
is_active_in intracellular membraneless organelle EXP
Inferred from Experiment
more info
 PubMed 
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 
located_in plasma membrane IEA
Inferred from Electronic Annotation
more info
  

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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NEW Try the new Transcript table

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

  1. NG_008212.3 RefSeqGene

    Range
    5001..17036
    Download
    GenBank, FASTA, Sequence Viewer (Graphics), LRG_322

mRNA and Protein(s)

  1. 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
    B2RE45, P40337, Q13599, Q6PDA9
    UniProtKB/TrEMBL
    A0A024R2F2, A0A0S2Z4I2, A0A8Q3SIA6
    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)

  2. 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
    Consensus CDS
    CCDS93209.1
    UniProtKB/TrEMBL
    A0A8Q3WL21
    Related
    ENSP00000512435.1, ENST00000696143.2
    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)

  3. 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/TrEMBL
    A0A0S2Z4K1
    Related
    ENSP00000344757.2, ENST00000345392.3
    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)

RNA

  1. NR_176335.1 RNA Sequence

    Status: REVIEWED

    Source sequence(s)
    AC034193
    Related
    ENST00000713814.1

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

  1. NC_000003.12 Reference GRCh38.p14 Primary Assembly

    Range
    10141778..10153667
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060927.1 Alternate T2T-CHM13v2.0

    Range
    10134670..10146564
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)
Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
P40337.2 GenPept UniProtKB/Swiss-Prot:P40337

Gene LinkOut

The following LinkOut resources are supplied by external providers. These providers are responsible for maintaining the links.

Chemical Information
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