ClinVar Genomic variation as it relates to human health
NM_001430.5(EPAS1):c.1609G>A (p.Gly537Arg)
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_001430.5(EPAS1):c.1609G>A (p.Gly537Arg)
Variation ID: 6469 Accession: VCV000006469.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 46380281 (GRCh38) [ NCBI UCSC ] 2: 46607420 (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 18, 2018 Apr 15, 2024 Mar 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001430.5:c.1609G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001421.2:p.Gly537Arg missense NC_000002.12:g.46380281G>A NC_000002.11:g.46607420G>A NG_016000.1:g.87880G>A Q99814:p.Gly537Arg - Protein change
- G537R
- Other names
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- Canonical SPDI
- NC_000002.12:46380280:G:A
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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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EPAS1 | - | - |
GRCh38 GRCh37 |
1195 | 1362 |
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, single submitter
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Mar 31, 2022 | RCV000006842.7 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 8, 2023 | RCV001532400.17 |
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
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Erythrocytosis, familial, 4
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767493.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with familial erythrocytosis 4 (MIM#611783) (PMID: 19208626). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER, PMIDs: 27292716, 19208626, 29790589). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Gly537Trp) has been observed in one family with erythrocytosis, and was seen to segregate in three affected family members (PMID: 18184961). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in more than ten individuals with erythrocytosis (ClinVar, PMID: 29790589). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Studies in TRex 293 cells have shown this variant displays a gain of function effect, increasing stabilization of the EPAS1 protein, and impairing binding to PHD2 and VHL (PMID: 19208626). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Mar 08, 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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Invitae
Accession: SCV002242810.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects EPAS1 function (PMID: 18650473, 19208626, 23716564). … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects EPAS1 function (PMID: 18650473, 19208626, 23716564). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 6469). This variant is also known as HIF2a c.2097G>A. This missense change has been observed in individual(s) with clinical features of erythrocytosis (PMID: 18378852, 18650473, 21389259, 23716564, 27651169). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 537 of the EPAS1 protein (p.Gly537Arg). (less)
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Pathogenic
(Mar 01, 2021)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001747953.14
First in ClinVar: Jul 10, 2021 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Apr 03, 2009)
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no assertion criteria provided
Method: literature only
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ERYTHROCYTOSIS, FAMILIAL, 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027038.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 08, 2019 |
Comment on evidence:
In 3 unrelated patients with erythrocytosis (ECYT4; 611783), Percy et al. (2008) identified a heterozygous 1609G-A transition in exon 12 of the EPAS1 gene, resulting … (more)
In 3 unrelated patients with erythrocytosis (ECYT4; 611783), Percy et al. (2008) identified a heterozygous 1609G-A transition in exon 12 of the EPAS1 gene, resulting in a gly537-to-arg (G537R) substitution in a conserved residue. The patients presented between age 16 and 21 years with increased hematocrit and elevated serum erythropoietin. One of the patients had an affected daughter. A different mutation was reported in this same codon (G537W; 603349.0001) in another family with erythrocytosis. In vitro functional expression assays performed by Furlow et al. (2009) showed that the G537R-mutant protein had decreased PHD2 (606425) binding and decreased hydroxylation compared to wildtype EPAS1. The G537R mutant was also less potent in competing for VHL (608537) binding. The mutant protein showed increased stability and decreased degradation associated with increased downstream transcriptional activity, consistent with a gain-of-function effect. Furlow et al. (2009) noted that the mutation occurs downstream of the hydroxylacceptor pro531 residue, indicating that these residues play a critical role in proper protein function. (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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Genotype-Phenotype Correlation of Hereditary Erythrocytosis Mutations, a single center experience. | Oliveira JL | American journal of hematology | 2018 | PMID: 29790589 |
Gene panel sequencing improves the diagnostic work-up of patients with idiopathic erythrocytosis and identifies new mutations. | Camps C | Haematologica | 2016 | PMID: 27651169 |
EPAS1 p.M535T mutation in a Bulgarian family with congenital erythrocytosis. | Alaikov T | Hematology (Amsterdam, Netherlands) | 2016 | PMID: 27292716 |
Congenital erythrocytosis associated with gain-of-function HIF2A gene mutations and erythropoietin levels in the normal range. | Perrotta S | Haematologica | 2013 | PMID: 23716564 |
Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2alpha gain-of-function mutation. | Formenti F | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 2011 | PMID: 21389259 |
Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline. | Furlow PW | The Journal of biological chemistry | 2009 | PMID: 19208626 |
Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2 alpha mutation. | Gale DP | Blood | 2008 | PMID: 18650473 |
Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis. | Percy MJ | Blood | 2008 | PMID: 18378852 |
A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. | Percy MJ | The New England journal of medicine | 2008 | PMID: 18184961 |
Text-mined citations for rs137853036 ...
HelpRecord last updated Apr 15, 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.