ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.467A>G (p.Tyr156Cys)
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.467A>G (p.Tyr156Cys)
Variation ID: 43600 Accession: VCV000043600.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.3 3: 10149790 (GRCh38) [ NCBI UCSC ] 3: 10191474 (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 May 1, 2024 Sep 1, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000551.4:c.467A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Tyr156Cys missense NM_001354723.2:c.*21A>G 3 prime UTR NM_198156.3:c.344A>G NP_937799.1:p.Tyr115Cys missense NC_000003.12:g.10149790A>G NC_000003.11:g.10191474A>G NG_008212.3:g.13156A>G NG_046756.1:g.7552A>G LRG_322:g.13156A>G LRG_322t1:c.467A>G LRG_322p1:p.Tyr156Cys P40337:p.Tyr156Cys - Protein change
- Y156C, Y115C
- Other names
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- Canonical SPDI
- NC_000003.12:10149789:A: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 |
829 | 1994 | |
LOC107303340 | - | - | - | GRCh38 | - | 1114 |
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 (3) |
criteria provided, single submitter
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Feb 3, 2016 | RCV000036543.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 28, 2017 | RCV000487045.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 8, 2022 | RCV000492752.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 1, 2022 | RCV000631280.10 |
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
(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: SCV000697518.1
First in ClinVar: Mar 08, 2016 Last updated: Mar 08, 2016 |
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Pathogenic
(Jun 28, 2017)
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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: SCV000568595.3
First in ClinVar: Apr 27, 2017 Last updated: Dec 19, 2017 |
Comment:
This variant is denoted VHL c.467A>G at the cDNA level, p.Tyr156Cys (Y156C) at the protein level, and results in the change of a Tyrosine to … (more)
This variant is denoted VHL c.467A>G at the cDNA level, p.Tyr156Cys (Y156C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant was observed in multiple individuals with pheochromocytoma (PCC) and/or paraganglioma (PGL), in both the sporadic and familial setting, several of whom had early-onset and/or bilateral disease (Neumann 2002, Bauters 2003, Gimenez-Roqueplo 2003, Amar 2005, Boedeker 2009, Gergics 2009, Pigny 2009, van Nederveen 2009, Van Slycke 2009, Nordstrom-O?Brien 2010, Kruizinga 2014, de Cubas 2015). This variant has also been observed in individuals with other features of von Hippel-Lindau syndrome (Olschwang 1998, Dollfus 2002, Erlic 2010). Favier et al. (2009) showed that PGL/PCC from carriers of VHL Tyr156Cys had an increase in lactate dehydrogenase activity compared to non-VHL PCC/PGL, and lacked expression of p53, which is stabilized and activated by the VHL protein, and TIGAR (TP53-induced glycolysis and apoptosis regulator) by immunohistochemistry. VHL Tyr156Cys was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. VHL Tyr156Cys occurs at a position that is conserved in mammals and is located in the elongin C binding/alpha-domain (Yuen 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the currently available evidence, we consider VHL Tyr156Cys to be pathogenic. (less)
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Pathogenic
(Sep 01, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000752308.7
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.Tyr156 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.Tyr156 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 12000816, 19763184), which suggests that this may be a clinically significant amino acid residue. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on VHL function (PMID: 19763184). 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: 43600). This missense change has been observed in individuals with pheochromocytoma and/or paraganglioma, likely representing von Hippel-Lindau syndrome type 2C (PMID: 12000816, 16314641, 19029228, 19336503, 20151405; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 156 of the VHL protein (p.Tyr156Cys). (less)
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Pathogenic
(Jun 08, 2022)
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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: SCV000580993.6
First in ClinVar: Jul 01, 2017 Last updated: May 01, 2024 |
Comment:
The p.Y156C pathogenic mutatio (also known as c.467A>G), located in coding exon 3 of the VHL gene, results from an A to G substitution at … (more)
The p.Y156C pathogenic mutatio (also known as c.467A>G), located in coding exon 3 of the VHL gene, results from an A to G substitution at nucleotide position 467. The tyrosine at codon 156 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in numerous von Hippel Lindau (VHL) cohorts, predominantly in individuals believed to have VHL type 2C, characterized by familial pheochromocytoma in the absence of other VHL-associated lesions (Amar L et al. J. Clin. Oncol. 2005 Dec; 23(34):8812-8; Olschwang S et al. Hum. Mutat. 1998; 12(6):424-30; Neumann HP et al. N. Engl. J. Med. 2002 May; 346(19):1459-66; Gergics P et al. Eur. J. Endocrinol. 2009 Sep; 161(3):495-502; Erlic Z et al. Endocr. Relat. Cancer. 2010 Dec; 17(4):875-83; Gallou C et al. Hum. Mutat. 2004 Sep; 24(3):215-24; Boedeker CC et al. J. Clin. Endocrinol. Metab. 2009 Jun; 94(6):1938-44; Kruizinga RC et al. Endocr. Relat. Cancer. 2014 Feb;21:63-71). However, at least one reported proband also had a retinal hemangioblastoma (Dollfus H et al. Invest. Ophthalmol. Vis. Sci. 2002 Sep; 43(9):3067-74), another had a pancreatic neuroendocrine tumor (Erlic Z et al. Endocr. Relat. Cancer. 2010 Dec; 17(4):875-83), and another also had a renal cyst (Kruizinga RC et al. Endocr. Relat. Cancer. 2014 Feb;21:63-71). Based on internal structural analysis, Y156C is deleterious and is mildly destabilizing to the local structure (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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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: SCV000264751.1
First in ClinVar: Mar 08, 2016 Last updated: Mar 08, 2016 |
Number of individuals with the variant: 11
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Pathogenic
(Aug 13, 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: SCV000060198.5
First in ClinVar: May 03, 2013 Last updated: Mar 08, 2016 |
Number of individuals with the variant: 2
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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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Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors. | Krauss T | Endocrine-related cancer | 2018 | PMID: 29748190 |
Calculating optimal surveillance for detection of von Hippel-Lindau-related manifestations. | Kruizinga RC | Endocrine-related cancer | 2013 | PMID: 24132471 |
Systematic comparison of sporadic and syndromic pancreatic islet cell tumors. | Erlic Z | Endocrine-related cancer | 2010 | PMID: 20660572 |
Genetic analysis of von Hippel-Lindau disease. | Nordstrom-O'Brien M | Human mutation | 2010 | PMID: 20151405 |
Local-regional recurrence of sporadic or syndromic abdominal extra-adrenal paraganglioma: incidence, characteristics, and outcome. | Van Slycke S | Surgery | 2009 | PMID: 19958924 |
The Warburg effect is genetically determined in inherited pheochromocytomas. | Favier J | PloS one | 2009 | PMID: 19763184 |
Germline VHL gene mutations in Hungarian families with von Hippel-Lindau disease and patients with apparently sporadic unilateral pheochromocytomas. | Gergics P | European journal of endocrinology | 2009 | PMID: 19574279 |
Head and neck paragangliomas in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. | Boedeker CC | The Journal of clinical endocrinology and metabolism | 2009 | PMID: 19336503 |
Should genetic testing be performed in each patient with sporadic pheochromocytoma at presentation? | Pigny P | European journal of endocrinology | 2009 | PMID: 19029228 |
Genetic testing in pheochromocytoma or functional paraganglioma. | Amar L | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2005 | PMID: 16314641 |
Genotype-phenotype correlation in von Hippel-Lindau families with renal lesions. | Gallou C | Human mutation | 2004 | PMID: 15300849 |
Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. | Gimenez-Roqueplo AP | Cancer research | 2003 | PMID: 14500403 |
Hereditary phaeochromocytomas and paragangliomas: a study of five susceptibility genes. | Bauters C | Journal of medical genetics | 2003 | PMID: 12807974 |
Retinal hemangioblastoma in von Hippel-Lindau disease: a clinical and molecular study. | Dollfus H | Investigative ophthalmology & visual science | 2002 | PMID: 12202531 |
Germ-line mutations in nonsyndromic pheochromocytoma. | Neumann HP | The New England journal of medicine | 2002 | PMID: 12000816 |
Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma. | Olschwang S | Human mutation | 1998 | PMID: 9829912 |
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Text-mined citations for rs397516441 ...
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.