ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.262T>C (p.Trp88Arg)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000551.4(VHL):c.262T>C (p.Trp88Arg)
Variation ID: 496053 Accession: VCV000496053.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.3 3: 10142109 (GRCh38) [ NCBI UCSC ] 3: 10183793 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 17, 2018 Feb 28, 2024 Aug 31, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000551.4:c.262T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Trp88Arg missense NM_001354723.2:c.262T>C NP_001341652.1:p.Trp88Arg missense NM_198156.3:c.262T>C NP_937799.1:p.Trp88Arg missense NC_000003.12:g.10142109T>C NC_000003.11:g.10183793T>C NG_008212.3:g.5475T>C LRG_322:g.5475T>C LRG_322t1:c.262T>C LRG_322p1:p.Trp88Arg - Protein change
- W88R
- Other names
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- Canonical SPDI
- NC_000003.12:10142108:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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VHL | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
830 | 2000 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2023 | RCV000589476.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 31, 2023 | RCV000631292.10 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Feb 03, 2016)
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criteria provided, single submitter
Method: clinical testing
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Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697494.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: This c.262T>C variant affects a conserved nucleotide, resulting in amino acid change from Trp to Arg. 5/5 in-silico tools predict this variant to … (more)
Variant summary: This c.262T>C variant affects a conserved nucleotide, resulting in amino acid change from Trp to Arg. 5/5 in-silico tools predict this variant to be damaging. This variant was not found in approximately 102034 control chromosomes, including the large and broad populations from ExAC. This variant has been reported in at least seven unrelated VHL patients and VHL-related tumors. c.262T>A, another variant leading to the same amino acid change, is a pathogenic variant. This evidence strongly supports that variant of interest is also pathogenic. In addition, codon 88 is a mutational hot spot in which other potentially pathogenic variants such as .W88C, p.W88S, p.W88* (c.263G>A) and p.W88* (c.264G>A) have been reported in VHL disease or its related cancers. In a tumor cell containing this variant, vascular endothelial growth factor (VEGF) expression was significantly increased which suggests that this variant leads to functional impairment (although it is uncertain whether observed effect was solely due to this variant as they assay was from patient cells) (Na_2003). Taken together, this variant has been classified as a Pathogenic. (less)
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Pathogenic
(Jan 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV003806644.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 31620170, 35448166, 12624160, 33720516, 17024664, … (more)
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 31620170, 35448166, 12624160, 33720516, 17024664, 17688370]. Functional studies indicate this variant impacts protein function [PMID: 35448166]. This variant is expected to disrupt protein structure [internal Myriad data]. (less)
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Pathogenic
(Aug 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Von Hippel-Lindau syndrome
Chuvash polycythemia
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000752320.7
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp88 amino acid residue in VHL. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp88 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7728151, 10567493, 11309459, 17024664, 19996202, 21715564, 27530247). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function. ClinVar contains an entry for this variant (Variation ID: 496053). This missense change has been observed in individuals with Von Hippel-Lindau syndrome (PMID: 7728151, 10567493, 11309459, 12624160, 17024664, 17688370, 19996202, 21715564, 27530247). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 88 of the VHL protein (p.Trp88Arg). (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Whole-Exome Sequencing Identifies the VHL Mutation (c.262T > C, p.Try88Arg) in Non-Obstructive Azoospermia-Associated Cystic Renal Cell Carcinoma. | Man Y | Current oncology (Toronto, Ont.) | 2022 | PMID: 35448166 |
Genotype-phenotype correlation in von Hippel-Lindau disease. | Reich M | Acta ophthalmologica | 2021 | PMID: 33720516 |
Frequent Mutations of VHL Gene and the Clinical Phenotypes in the Largest Chinese Cohort With Von Hippel-Lindau Disease. | Hong B | Frontiers in genetics | 2019 | PMID: 31620170 |
Characterization of VHL missense mutations in sporadic clear cell renal cell carcinoma: hotspots, affected binding domains, functional impact on pVHL and therapeutic relevance. | Razafinjatovo C | BMC cancer | 2016 | PMID: 27530247 |
Clinical and pathologic impact of select chromatin-modulating tumor suppressors in clear cell renal cell carcinoma. | Hakimi AA | European urology | 2013 | PMID: 23036577 |
BAP1 loss defines a new class of renal cell carcinoma. | Peña-Llopis S | Nature genetics | 2012 | PMID: 22683710 |
VHL gene mutations and their effects on hypoxia inducible factor HIFα: identification of potential driver and passenger mutations. | Rechsteiner MP | Cancer research | 2011 | PMID: 21715564 |
Analysis of VHL Gene Alterations and their Relationship to Clinical Parameters in Sporadic Conventional Renal Cell Carcinoma. | Young AC | Clinical cancer research : an official journal of the American Association for Cancer Research | 2009 | PMID: 19996202 |
Clinical characteristics of renal cell carcinoma in Korean patients with von Hippel-Lindau disease compared to sporadic bilateral or multifocal renal cell carcinoma. | Kim WT | Journal of Korean medical science | 2009 | PMID: 19949673 |
Structural bioinformatics mutation analysis reveals genotype-phenotype correlations in von Hippel-Lindau disease and suggests molecular mechanisms of tumorigenesis. | Forman JR | Proteins | 2009 | PMID: 19408298 |
Germline VHL gene mutations in three Serbian families with von Hippel-Lindau disease. | Stanojevic BR | Neoplasma | 2007 | PMID: 17688370 |
Genotype-phenotype correlations in von Hippel-Lindau disease. | Ong KR | Human mutation | 2007 | PMID: 17024664 |
Overproduction of vascular endothelial growth factor related to von Hippel-Lindau tumor suppressor gene mutations and hypoxia-inducible factor-1 alpha expression in renal cell carcinomas. | Na X | The Journal of urology | 2003 | PMID: 12853836 |
High frequency of novel germline mutations in the VHL gene in the heterogeneous population of Brazil. | Rocha JC | Journal of medical genetics | 2003 | PMID: 12624160 |
Reconsideration of biallelic inactivation of the VHL tumour suppressor gene in hemangioblastomas of the central nervous system. | Gläsker S | Journal of neurology, neurosurgery, and psychiatry | 2001 | PMID: 11309459 |
VHL alterations in human clear cell renal cell carcinoma: association with advanced tumor stage and a novel hot spot mutation. | Brauch H | Cancer research | 2000 | PMID: 10766184 |
The impact of molecular genetic analysis of the VHL gene in patients with haemangioblastomas of the central nervous system. | Gläsker S | Journal of neurology, neurosurgery, and psychiatry | 1999 | PMID: 10567493 |
Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. | Chen F | Human mutation | 1995 | PMID: 7728151 |
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Text-mined citations for rs1553619431 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.