ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.264G>T (p.Trp88Cys)
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.264G>T (p.Trp88Cys)
Variation ID: 223171 Accession: VCV000223171.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.3 3: 10142111 (GRCh38) [ NCBI UCSC ] 3: 10183795 (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 9, 2016 Feb 28, 2024 Jul 3, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000551.4:c.264G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Trp88Cys missense NM_001354723.2:c.264G>T NP_001341652.1:p.Trp88Cys missense NM_198156.3:c.264G>T NP_937799.1:p.Trp88Cys missense NC_000003.12:g.10142111G>T NC_000003.11:g.10183795G>T NG_008212.3:g.5477G>T LRG_322:g.5477G>T LRG_322t1:c.264G>T LRG_322p1:p.Trp88Cys - Protein change
- W88C
- Other names
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- Canonical SPDI
- NC_000003.12:10142110:G:T
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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 |
802 | 1957 |
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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Likely pathogenic (2) |
criteria provided, single submitter
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Mar 27, 2018 | RCV000208827.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 3, 2023 | RCV000492552.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 8, 2022 | RCV000537014.8 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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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Likely pathogenic
(Mar 27, 2018)
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criteria provided, single submitter
Method: clinical testing
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Von Hippel-Lindau syndrome
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967005.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Trp88Cys variant in VHL has been reported in at least 5 individuals with v on Hippel-Landau syndrome (VHL; Glasker 1999, Clinvar Variation ID: 223171), … (more)
The p.Trp88Cys variant in VHL has been reported in at least 5 individuals with v on Hippel-Landau syndrome (VHL; Glasker 1999, Clinvar Variation ID: 223171), and was absent from large population studies. In vitro functional studies provide s ome evidence that the p.Trp88Cys variant may impact protein function (Reschestei ner 2011). Computational prediction tools and conservation analysis suggest that the p.Trp88Cys variant may impact the protein. Additionally, other missense va riants at this position (p.Trp88Arg and p.Trp88Ser) have been reported in indivi duals with VHL (Glasker 2001, Rocha 2003, Chen 1995, Ong 2007, Jilg 2012, Stanoj evic 2007, Wong 2016), suggesting that a change at this amino acid position is n ot tolerated. In summary, although additional studies are required to fully esta blish its clinical significance, the p.Trp88Cys variant is likely pathogenic. AC MG/AMP criteria applied (Richards 2015): PM2; PM5; PP3; PS3_supporting; PS4_supp orting. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Jul 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000580958.6
First in ClinVar: Jul 01, 2017 Last updated: Oct 28, 2023 |
Comment:
The p.W88C variant (also known as c.264G>T), located in coding exon 1 of the VHL gene, results from a G to T substitution at nucleotide … (more)
The p.W88C variant (also known as c.264G>T), located in coding exon 1 of the VHL gene, results from a G to T substitution at nucleotide position 264. The tryptophan at codon 88 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in a cohort of over 25,000 individuals who underwent multigene panel testing (eMERGE Consortium. Am J Hum Genet, 2019 09;105:588-605). A similar alteration resulting in the same amino acid change (W88C) but with a different nucleotide change (referred to as 477G/C) has been reported in one individual diagnosed with CNS hemangioblastomas (Gläsker S et al. J. Neurol. Neurosurg. Psychiatr. 1999 Dec;67(6):758-62). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Mar 08, 2022)
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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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Invitae
Accession: SCV000626890.7
First in ClinVar: Dec 26, 2017 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, 8956040, 10567493, 17024664). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects VHL function (PMID: 21715564). 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: 223171). This missense change has been observed in individuals with clinical features of von Hippel-Lindau (VHL) syndrome (PMID: 10567493; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 88 of the VHL protein (p.Trp88Cys). (less)
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Likely pathogenic
(Feb 26, 2016)
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no assertion criteria provided
Method: clinical testing
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Von Hippel-Lindau syndrome
Affected status: yes
Allele origin:
germline
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000264688.1
First in ClinVar: Mar 09, 2016 Last updated: Mar 09, 2016 |
Number of individuals with the variant: 5
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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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Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
Clinical and molecular characteristics of East Asian patients with von Hippel-Lindau syndrome. | Wong M | Chinese journal of cancer | 2016 | PMID: 27527340 |
Growth kinetics in von Hippel-Lindau-associated renal cell carcinoma. | Jilg CA | Urologia internationalis | 2012 | PMID: 22156657 |
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 |
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 |
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 |
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 (VHL) gene in families from North America, Europe, and Japan. | Zbar B | Human mutation | 1996 | PMID: 8956040 |
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 rs869025622 ...
HelpRecord last updated Feb 28, 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.