ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.194C>G (p.Ser65Trp)
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.194C>G (p.Ser65Trp)
Variation ID: 43597 Accession: VCV000043597.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.3 3: 10142041 (GRCh38) [ NCBI UCSC ] 3: 10183725 (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 8, 2016 Feb 28, 2024 Dec 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000551.4:c.194C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Ser65Trp missense NM_001354723.2:c.194C>G NP_001341652.1:p.Ser65Trp missense NM_198156.3:c.194C>G NP_937799.1:p.Ser65Trp missense NC_000003.12:g.10142041C>G NC_000003.11:g.10183725C>G NG_008212.3:g.5407C>G LRG_322:g.5407C>G LRG_322t1:c.194C>G LRG_322p1:p.Ser65Trp P40337:p.Ser65Trp - Protein change
- S65W
- Other names
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- Canonical SPDI
- NC_000003.12:10142040:C:G
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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 |
790 | 1944 |
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
Help
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) |
no assertion criteria provided
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Feb 26, 2016 | RCV000036539.7 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000497340.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 7, 2021 | RCV002415465.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 17, 2023 | RCV001219547.8 |
Submissions - Germline
Classification
Help
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
(Jun 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000589600.3
First in ClinVar: Aug 20, 2017 Last updated: Jul 01, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: decreased VHL protein binding to HIF-1alpha, preventing ubiquitination (Miller 2005); Observed in multiple individuals with history consistent with … (more)
Published functional studies demonstrate a damaging effect: decreased VHL protein binding to HIF-1alpha, preventing ubiquitination (Miller 2005); Observed in multiple individuals with history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (Stolle 1998, Hes 2007, Dandanell 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17661816, 20233476, 27527340, 26622630, 30731206, 23384228, 18544564, 15611064, 9829911, 19602254, 22799452, 10567493, 24444636, 8730290, 25563310, 7987306, 15881703, 31176917, 30522901, 31620170) (less)
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Pathogenic
(Oct 07, 2021)
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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: SCV002718251.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.S65W pathogenic mutation (also known as c.194C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at … (more)
The p.S65W pathogenic mutation (also known as c.194C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 194. The serine at codon 65 is replaced by tryptophan, an amino acid with highly dissimilar properties This alteration has been reported as a germline mutation in many families affected with von Hippel-Lindau (VHL) syndrome that had no history of pheochromocytomas (Zbar et al. Hum Mutat. 1996;8(4):348-57; Crossey et al. Hum Mol Genet. 1994 Aug;3(8):1303-8; Ong et al. Hum Mutat. 2007 Feb;28(2):143-9; Zhang et al. J Cancer Res Clin Oncol. 2008 Nov;134(11):1211-8; Zhou et al. Pathol Int. 2010 Jun;60(6):452-8; Hes FJ et al. Clin. Genet., 2007 Aug;72:122-9). It has also been reported as a de novo alteration in a Chinese individual diagnosed with bilateral renal cell carcinoma at the age of 33 (Zhang L et al. Oncol Lett, 2015 Aug;10:1087-1090). Functional studies have indicated that the p.S65W mutation leads to severely compromised tight junctions and an unstable protein, therefore classifying it as a Type 1 VHL mutation (Bangiyeva et al. BMC Cancer. 2009 Jul 14;9:229). Note that this alteration is also referred to as c.407C>G in some published literature. Based on the available evidence, p.S65W is classified as a pathogenic mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Dec 17, 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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Invitae
Accession: SCV001391491.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 65 of the VHL protein … (more)
This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 65 of the VHL protein (p.Ser65Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Von Hippel-Lindau (VHL) syndrome (PMID: 7728151, 7987306, 8730290, 9829911, 10567493, 17024664, 22799452, 23384228). This variant is also known as Ser136Trp. ClinVar contains an entry for this variant (Variation ID: 43597). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects VHL function (PMID: 11331613, 15611064, 16669786, 18544564, 19602254). This variant disrupts the p.Ser65 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10567493, 12114495, 15611064, 22799452, 25282218). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002552398.4
First in ClinVar: Jul 27, 2022 Last updated: Aug 18, 2023 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931418.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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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: SCV000264669.1
First in ClinVar: Mar 08, 2016 Last updated: Mar 08, 2016 |
Number of individuals with the variant: 4
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Pathogenic
(Jul 30, 2008)
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no assertion criteria provided
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: SCV000060194.5
First in ClinVar: May 03, 2013 Last updated: Mar 08, 2016 |
Number of individuals with the variant: 1
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001970464.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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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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Advanced renal cell carcinoma associated with von Hippel-Lindau disease: A case report and review of the literature. | Zhang L | Oncology letters | 2015 | PMID: 26622630 |
Multiple lung adenocarcinomas associated with von hippel-lindau disease. | Ikeda K | The Annals of thoracic surgery | 2014 | PMID: 25282218 |
Mosaicism in von Hippel-Lindau disease with severe renal manifestations. | Wu P | Clinical genetics | 2013 | PMID: 23384228 |
Identification of 3 novel VHL germ-line mutations in Danish VHL patients. | Dandanell M | BMC medical genetics | 2012 | PMID: 22799452 |
Differences in regulation of tight junctions and cell morphology between VHL mutations from disease subtypes. | Bangiyeva V | BMC cancer | 2009 | PMID: 19602254 |
Hypoxia-inducible factor-2alpha regulates the expression of TRAIL receptor DR5 in renal cancer cells. | Mahajan S | Carcinogenesis | 2008 | PMID: 18544564 |
Frequency of Von Hippel-Lindau germline mutations in classic and non-classic Von Hippel-Lindau disease identified by DNA sequencing, Southern blot analysis and multiplex ligation-dependent probe amplification. | Hes FJ | Clinical genetics | 2007 | PMID: 17661816 |
Genotype-phenotype correlations in von Hippel-Lindau disease. | Ong KR | Human mutation | 2007 | PMID: 17024664 |
The von Hippel-Lindau tumour-suppressor protein interaction with protein kinase Cdelta. | Iturrioz X | The Biochemical journal | 2006 | PMID: 16669786 |
Inactivation of VHL by tumorigenic mutations that disrupt dynamic coupling of the pVHL.hypoxia-inducible transcription factor-1alpha complex. | Miller F | The Journal of biological chemistry | 2005 | PMID: 15611064 |
[von Hippel-Lindau syndrome: molecular diagnosis of two Lebanese families and analysis of the genotype-phenotype correlation]. | Medlej-Hashim M | Le Journal medical libanais. The Lebanese medical journal | 2004 | PMID: 15881703 |
Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene. | Cybulski C | Journal of medical genetics | 2002 | PMID: 12114495 |
Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. | Clifford SC | Human molecular genetics | 2001 | PMID: 11331613 |
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 |
Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. | Stolle C | Human mutation | 1998 | PMID: 9829911 |
Phenotypic expression in von Hippel-Lindau disease: correlations with germline VHL gene mutations. | Maher ER | Journal of medical genetics | 1996 | PMID: 8730290 |
Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. | Chen F | Human mutation | 1995 | PMID: 7728151 |
Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. | Crossey PA | Human molecular genetics | 1994 | PMID: 7987306 |
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Text-mined citations for rs5030826 ...
HelpRecord last updated Mar 05, 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.