ClinVar Genomic variation as it relates to human health
NM_001943.5(DSG2):c.1520G>A (p.Cys507Tyr)
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_001943.5(DSG2):c.1520G>A (p.Cys507Tyr)
Variation ID: 16813 Accession: VCV000016813.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31536298 (GRCh38) [ NCBI UCSC ] 18: 29116261 (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 May 13, 2017 May 1, 2024 Mar 14, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001943.5:c.1520G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001934.2:p.Cys507Tyr missense NC_000018.10:g.31536298G>A NC_000018.9:g.29116261G>A NG_007072.3:g.43057G>A LRG_397:g.43057G>A LRG_397t1:c.1520G>A LRG_397p1:p.Cys507Tyr Q14126:p.Cys507Tyr - Protein change
- C507Y
- Other names
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C506Y
- Canonical SPDI
- NC_000018.10:31536297: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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The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
- Comment on variant
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
Help
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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DSG2 | Some evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1115 | 1922 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Mar 14, 2024 | RCV000018306.47 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 30, 2023 | RCV001178344.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 28, 2021 | RCV002390115.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 7, 2023 | RCV001588816.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 8, 2022 | RCV002476988.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 5, 2024 | RCV003996107.2 |
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
Help
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
Help
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
Help
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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Uncertain significance
(Apr 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 10
Dilated cardiomyopathy 1BB
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002784108.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Aug 07, 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: SCV001824069.2
First in ClinVar: Sep 08, 2021 Last updated: Aug 18, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein … (more)
Not observed at a 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: 16773573, 20152563, 20857253, 20031617, 23671136, 23871885, 31737537, 31402444, 32665702) (less)
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Uncertain significance
(Apr 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 10
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001395117.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more)
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DSG2 protein function. ClinVar contains an entry for this variant (Variation ID: 16813). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20031617, 20152563, 31737537). This variant is present in population databases (rs121913009, gnomAD 0.01%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 507 of the DSG2 protein (p.Cys507Tyr). (less)
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Uncertain significance
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001342755.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces cysteine with tyrosine at codon 507 of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces cysteine with tyrosine at codon 507 of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least four individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16773573, 20152563, 23871885, 31737537). This variant has been identified in 2/280834 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Mar 14, 2024)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 10
Affected status: yes
Allele origin:
unknown
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KardioGenetik, Herz- und Diabeteszentrum NRW
Accession: SCV004809102.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Comment:
Patient is also carrier of DSG stop variant
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Number of individuals with the variant: 1
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Uncertain Significance
(Feb 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004819554.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces cysteine with tyrosine at codon 507 of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces cysteine with tyrosine at codon 507 of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least four individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20031617, 20152563, 20857253; Marschall et al, 2019). This variant has been identified in 2/280834 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 2
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Uncertain significance
(May 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002705311.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.C507Y variant (also known as c.1520G>A), located in coding exon 11 of the DSG2 gene, results from a G to A substitution at nucleotide … (more)
The p.C507Y variant (also known as c.1520G>A), located in coding exon 11 of the DSG2 gene, results from a G to A substitution at nucleotide position 1520. The cysteine at codon 507 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been detected in an individual reported to have arrhythmogenic right ventricular cardiomyopathy (ARVC) and in cases referred for ARVC genetic testing (Awad MM et al. Am. J. Hum. Genet., 2006 Jul;79:136-42 (reported as C506Y); Marschall C et al. Cardiovasc Diagn Ther. 2019 Oct;9(Suppl 2):S292-S298). This variant has also been detected in several individuals from exome sequencing cohorts who were not know to have ARVC (Haggerty CM et al. Genet. Med., 2017 11;19:1245-1252; van Rooij J et al. Genet Med. 2020 11;22(11):1812-1820). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Pathogenic
(Jul 01, 2006)
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no assertion criteria provided
Method: literature only
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ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 10
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038585.3
First in ClinVar: Apr 04, 2013 Last updated: May 13, 2017 |
Comment on evidence:
In a patient with arrhythmogenic right ventricular dysplasia (ARVD10; 610193), Awad et al. (2006) identified a heterozygous G-to-A transition at nucleotide 1517 in exon 11 … (more)
In a patient with arrhythmogenic right ventricular dysplasia (ARVD10; 610193), Awad et al. (2006) identified a heterozygous G-to-A transition at nucleotide 1517 in exon 11 of the DSG2 gene that caused a cys506-to-tyr (C506Y) substitution in desmoglein-2. (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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Reduced penetrance of pathogenic ACMG variants in a deeply phenotyped cohort study and evaluation of ClinVar classification over time. | van Rooij J | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32665702 |
Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders. | Marschall C | Cardiovascular diagnosis and therapy | 2019 | PMID: 31737537 |
Implantable Cardioverter-Defibrillator Therapy in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Predictors of Appropriate Therapy, Outcomes, and Complications. | Orgeron GM | Journal of the American Heart Association | 2017 | PMID: 28588093 |
Electronic health record phenotype in subjects with genetic variants associated with arrhythmogenic right ventricular cardiomyopathy: a study of 30,716 subjects with exome sequencing. | Haggerty CM | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28471438 |
Characterizing the Molecular Pathology of Arrhythmogenic Cardiomyopathy in Patient Buccal Mucosa Cells. | Asimaki A | Circulation. Arrhythmia and electrophysiology | 2016 | PMID: 26850880 |
Clinical Presentation, Long-Term Follow-Up, and Outcomes of 1001 Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Patients and Family Members. | Groeneweg JA | Circulation. Cardiovascular genetics | 2015 | PMID: 25820315 |
Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers. | James CA | Journal of the American College of Cardiology | 2013 | PMID: 23871885 |
Risk stratification in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers. | Bhonsale A | Circulation. Arrhythmia and electrophysiology | 2013 | PMID: 23671136 |
Shared desmosome gene findings in early and late onset arrhythmogenic right ventricular dysplasia/cardiomyopathy. | Tan BY | Journal of cardiovascular translational research | 2010 | PMID: 20857253 |
Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. | Xu T | Journal of the American College of Cardiology | 2010 | PMID: 20152563 |
Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy. | den Haan AD | Circulation. Cardiovascular genetics | 2009 | PMID: 20031617 |
DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy. | Awad MM | American journal of human genetics | 2006 | PMID: 16773573 |
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Text-mined citations for rs121913009 ...
HelpRecord last updated Nov 10, 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.
NCBI staff reviewed the sequence information reported in PubMed 16773573 to determine the location of this allele on current reference sequence.