VHL
von Hippel-Lindau tumor suppressor
Basic information
Region (hg38): 3:10141777-10153667
Links
Phenotypes
GenCC
Source:
- von Hippel-Lindau disease (Strong), mode of inheritance: AD
- renal cell carcinoma (Strong), mode of inheritance: AD
- Chuvash polycythemia (Strong), mode of inheritance: AR
- von Hippel-Lindau disease (Supportive), mode of inheritance: AD
- hereditary pheochromocytoma-paraganglioma (Supportive), mode of inheritance: AD
- Chuvash polycythemia (Supportive), mode of inheritance: AR
- von Hippel-Lindau disease (Definitive), mode of inheritance: AD
- Chuvash polycythemia (Strong), mode of inheritance: AR
- von Hippel-Lindau disease (Strong), mode of inheritance: AD
- von Hippel-Lindau disease (Definitive), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Von Hippel Lindau; Erythrocytosis, familial, 2 (Chuvash polycythemia); Pheochromocytoma | AD/AR | Cardiovascular; Hematologic; Oncologic | 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 | Cardiovascular; Hematologic; Oncologic | 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; 23968328 |
| Depending on the condition, individuals can have primarily oncologic (Von Hippel Lindau) or hematologic (Chuvash polycythemia) manifestations |
ClinVar
This is a list of variants' phenotypes submitted to
- Chuvash polycythemia;Von Hippel-Lindau syndrome (730 variants)
- Hereditary cancer-predisposing syndrome (604 variants)
- Von Hippel-Lindau syndrome (488 variants)
- Von Hippel-Lindau syndrome;Chuvash polycythemia (397 variants)
- not provided (292 variants)
- not specified (98 variants)
- Chuvash polycythemia (74 variants)
- VHL-related condition (18 variants)
- Pheochromocytoma (10 variants)
- Pheochromocytoma;Von Hippel-Lindau syndrome;Nonpapillary renal cell carcinoma;Chuvash polycythemia (7 variants)
- Chuvash polycythemia;Pheochromocytoma;Von Hippel-Lindau syndrome;Nonpapillary renal cell carcinoma (5 variants)
- Von Hippel-Lindau syndrome;Nonpapillary renal cell carcinoma;Pheochromocytoma;Chuvash polycythemia (4 variants)
- Papillary renal cell carcinoma type 1 (3 variants)
- Pheochromocytoma;Chuvash polycythemia;Von Hippel-Lindau syndrome;Nonpapillary renal cell carcinoma (3 variants)
- Chuvash polycythemia;Nonpapillary renal cell carcinoma;Von Hippel-Lindau syndrome;Pheochromocytoma (3 variants)
- Pheochromocytoma;Nonpapillary renal cell carcinoma;Chuvash polycythemia;Von Hippel-Lindau syndrome (3 variants)
- Chuvash polycythemia;Von Hippel-Lindau syndrome;Nonpapillary renal cell carcinoma;Pheochromocytoma (3 variants)
- Enchondromatosis (3 variants)
- Chuvash polycythemia;Von Hippel-Lindau syndrome;Pheochromocytoma;Nonpapillary renal cell carcinoma (3 variants)
- Neoplasm (3 variants)
- Ovarian cancer (2 variants)
- Von Hippel-Lindau syndrome;Chuvash polycythemia;Pheochromocytoma;Nonpapillary renal cell carcinoma (2 variants)
- Maffucci syndrome (2 variants)
- Pheochromocytoma;Von Hippel-Lindau syndrome;Chuvash polycythemia;Nonpapillary renal cell carcinoma (2 variants)
- Hepatoblastoma (2 variants)
- Von Hippel-Lindau syndrome;Chuvash polycythemia;Nonpapillary renal cell carcinoma;Pheochromocytoma (2 variants)
- Chuvash polycythemia;Nonpapillary renal cell carcinoma;Pheochromocytoma;Von Hippel-Lindau syndrome (2 variants)
- Nonpapillary renal cell carcinoma;Chuvash polycythemia;Pheochromocytoma;Von Hippel-Lindau syndrome (1 variants)
- Familial infantile myasthenia (1 variants)
- Chuvash polycythemia;Pheochromocytoma;Nonpapillary renal cell carcinoma;Von Hippel-Lindau syndrome (1 variants)
- Von Hippel-Lindau syndrome;Nonpapillary renal cell carcinoma;Chuvash polycythemia;Pheochromocytoma (1 variants)
- Acute leukemia of ambiguous lineage (1 variants)
- Nonpapillary renal cell carcinoma;Von Hippel-Lindau syndrome;Chuvash polycythemia;Pheochromocytoma (1 variants)
- Inborn genetic diseases (1 variants)
- Pheochromocytoma;Chuvash polycythemia;Nonpapillary renal cell carcinoma;Von Hippel-Lindau syndrome (1 variants)
- Von Hippel-Lindau syndrome;Pheochromocytoma;Nonpapillary renal cell carcinoma;Chuvash polycythemia (1 variants)
- Polycythemia (1 variants)
- Diffuse midline glioma, H3 K27-altered (1 variants)
- Nonpapillary renal cell carcinoma (1 variants)
- Renal cell carcinoma with paraneoplastic erythrocytosis (1 variants)
- Au-Kline syndrome (1 variants)
- Nonpapillary renal cell carcinoma;Pheochromocytoma;Von Hippel-Lindau syndrome;Chuvash polycythemia (1 variants)
- Retinal capillary hemangioma;Spinal hemangioblastoma;Pancreatic cysts;Cerebellar hemangioblastoma (1 variants)
- Nonpapillary renal cell carcinoma;Pheochromocytoma;Chuvash polycythemia;Von Hippel-Lindau syndrome (1 variants)
- Congenital Erythrocytosis (1 variants)
- Lung sarcomatoid carcinoma (1 variants)
- Pancreatic cysts;Renal cyst (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the VHL gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 202 | 207 | ||||
| missense | 70 | 72 | 396 | 542 | ||
| nonsense | 29 | 15 | 48 | |||
| start loss | 4 | |||||
| frameshift | 73 | 18 | 14 | 105 | ||
| inframe indel | 24 | 30 | ||||
| splice donor/acceptor (+/-2bp) | 13 | 15 | ||||
| splice region ? | 15 | 14 | 29 | |||
| non coding ? | 349 | 94 | 70 | 516 | ||
| Total | 189 | 103 | 804 | 300 | 71 |
Highest pathogenic variant AF is 0.00000657
Variants in VHL
This is a list of pathogenic ClinVar variants found in the VHL region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 3-10141778-G-A | Von Hippel-Lindau syndrome | Likely benign (Aug 23, 2023) | ||
| 3-10141782-C-CTCCGCCCCGCG | not specified • Chuvash polycythemia;Von Hippel-Lindau syndrome • Hereditary cancer-predisposing syndrome • VHL-related disorder • Chuvash polycythemia | Conflicting classifications of pathogenicity (Apr 04, 2024) | ||
| 3-10141784-C-T | Von Hippel-Lindau syndrome • Hereditary cancer-predisposing syndrome • Chuvash polycythemia;Von Hippel-Lindau syndrome • VHL-related disorder | Conflicting classifications of pathogenicity (May 30, 2023) | ||
| 3-10141785-CGCCCCGCGTCCGACCCGCGG-C | Uncertain significance (Mar 01, 2023) | |||
| 3-10141787-C-CCCCGCGTCCGACCCGCGGAT | Hereditary cancer-predisposing syndrome • VHL-related disorder | Conflicting classifications of pathogenicity (Apr 15, 2022) | ||
| 3-10141790-CGCGTCCGACCCGCGGATCCCGCG-C | Von Hippel-Lindau syndrome | Uncertain significance (Feb 24, 2023) | ||
| 3-10141790-C-CGCGTCCGACCCGCGGATCCCGCG | Von Hippel-Lindau syndrome | Uncertain significance (Dec 13, 2023) | ||
| 3-10141792-CG-C | Von Hippel-Lindau syndrome • Von Hippel-Lindau syndrome;Chuvash polycythemia | Uncertain significance (Dec 14, 2023) | ||
| 3-10141797-G-A | Chuvash polycythemia;Von Hippel-Lindau syndrome | Uncertain significance (Dec 15, 2023) | ||
| 3-10141799-C-T | Chuvash polycythemia;Von Hippel-Lindau syndrome | Uncertain significance (Jan 21, 2024) | ||
| 3-10141800-C-G | not specified | Likely benign (Jul 28, 2017) | ||
| 3-10141800-C-T | Chuvash polycythemia;Von Hippel-Lindau syndrome | Uncertain significance (Dec 26, 2023) | ||
| 3-10141801-C-G | not specified | Likely benign (Jan 07, 2016) | ||
| 3-10141801-C-T | not specified • Chuvash polycythemia;Von Hippel-Lindau syndrome | Conflicting classifications of pathogenicity (Dec 08, 2023) | ||
| 3-10141803-C-A | VHL-related disorder • Von Hippel-Lindau syndrome;Chuvash polycythemia | Conflicting classifications of pathogenicity (Dec 12, 2023) | ||
| 3-10141803-C-T | Von Hippel-Lindau syndrome;Chuvash polycythemia | Uncertain significance (Dec 16, 2023) | ||
| 3-10141803-CGGATCCCGCGGCGTCCGGCCCGGGTGGTCT-C | Chuvash polycythemia;Von Hippel-Lindau syndrome • Von Hippel-Lindau syndrome | Uncertain significance (Dec 15, 2023) | ||
| 3-10141804-G-A | Chuvash polycythemia;Von Hippel-Lindau syndrome | Uncertain significance (Jan 21, 2024) | ||
| 3-10141804-G-T | not specified | Likely benign (Feb 14, 2017) | ||
| 3-10141808-C-T | not specified | Likely benign (Mar 15, 2016) | ||
| 3-10141810-C-T | not specified | Likely benign (Jun 16, 2016) | ||
| 3-10141812-C-G | not specified | Likely benign (Aug 30, 2017) | ||
| 3-10141812-C-T | not specified | Likely benign (Nov 03, 2017) | ||
| 3-10141813-G-A | not specified • Von Hippel-Lindau syndrome | Conflicting classifications of pathogenicity (Aug 15, 2023) | ||
| 3-10141817-T-C | VHL-related disorder | Likely benign (Jan 31, 2023) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| VHL | protein_coding | protein_coding | ENST00000256474 | 3 | 11213 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.0795 | 0.877 | 125746 | 0 | 2 | 125748 | 0.00000795 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | -0.395 | 136 | 124 | 1.10 | 0.00000675 | 1340 |
| Missense in Polyphen | 44 | 41.957 | 1.0487 | 479 | ||
| Synonymous | -0.630 | 63 | 57.0 | 1.11 | 0.00000307 | 440 |
| Loss of Function | 1.72 | 3 | 8.36 | 0.359 | 4.47e-7 | 83 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.00 | 0.00 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.00 | 0.00 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.00000879 | 0.00000879 |
| Middle Eastern | 0.00 | 0.00 |
| South Asian | 0.0000653 | 0.0000327 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- 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.;
- Pathway
- 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;Amplification and Expansion of Oncogenic Pathways as Metastatic Traits;Pathways in clear cell renal cell carcinoma;Type 2 papillary renal cell carcinoma;Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha;Regulation of Hypoxia-inducible Factor (HIF) by oxygen;Cellular response to hypoxia;hypoxia-inducible factor in the cardivascular system;vegf hypoxia and angiogenesis;Cellular responses to stress;Post-translational protein modification;Metabolism of proteins;HIF-2-alpha transcription factor network;Immune System;Adaptive Immune System;Hypoxic and oxygen homeostasis regulation of HIF-1-alpha;Antigen processing: Ubiquitination & Proteasome degradation;Class I MHC mediated antigen processing & presentation;Cellular responses to external stimuli;Neddylation
(Consensus)
Intolerance Scores
- loftool
- 0.0364
- rvis_EVS
- 0.06
- rvis_percentile_EVS
- 58.26
Haploinsufficiency Scores
- pHI
- 0.114
- hipred
- Y
- hipred_score
- 0.632
- ghis
- 0.571
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- E
- essential_gene_gene_trap
- H
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.973
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Vhl
- Phenotype
- normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); neoplasm; embryo phenotype; liver/biliary system phenotype; immune system phenotype; renal/urinary system phenotype; skeleton phenotype; limbs/digits/tail phenotype; digestive/alimentary phenotype; vision/eye phenotype; craniofacial phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; endocrine/exocrine gland phenotype; cellular phenotype; homeostasis/metabolism phenotype; muscle phenotype;
Zebrafish Information Network
- Gene name
- vhl
- Affected structure
- hematopoietic multipotent progenitor cell
- Phenotype tag
- abnormal
- Phenotype quality
- increased amount
Gene ontology
- Biological process
- negative regulation of transcription by RNA polymerase II;cell morphogenesis;regulation of transcription, DNA-templated;proteolysis;negative regulation of cell population proliferation;negative regulation of gene expression;protein ubiquitination;negative regulation of apoptotic process;post-translational protein modification;positive regulation of cell differentiation;positive regulation of transcription, DNA-templated;negative regulation of JAK-STAT cascade;protein stabilization;regulation of transcription from RNA polymerase II promoter in response to hypoxia;negative regulation of transcription from RNA polymerase II promoter in response to hypoxia
- Cellular component
- nucleus;nucleoplasm;mitochondrion;endoplasmic reticulum;cytosol;membrane;VCB complex
- Molecular function
- ubiquitin-protein transferase activity;protein binding;transcription factor binding;enzyme binding;ubiquitin protein ligase activity