ClinVar Genomic variation as it relates to human health
NM_001943.5(DSG2):c.1478A>G (p.Asn493Ser)
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.
Uncertain significance(9); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001943.5(DSG2):c.1478A>G (p.Asn493Ser)
Variation ID: 163212 Accession: VCV000163212.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31536256 (GRCh38) [ NCBI UCSC ] 18: 29116219 (GRCh37) [ NCBI UCSC ] 18: 27370217 (NCBI36) [ 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 Sep 14, 2015 Feb 20, 2024 Jan 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001943.5:c.1478A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001934.2:p.Asn493Ser missense NC_000018.10:g.31536256A>G NC_000018.9:g.29116219A>G NG_007072.3:g.43015A>G LRG_397:g.43015A>G LRG_397t1:c.1478A>G - Protein change
- N493S
- Other names
- p.N493S:AAC>AGC
- Canonical SPDI
- NC_000018.10:31536255: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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00006
The Genome Aggregation Database (gnomAD) 0.00011
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00017
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
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 |
1016 | 1760 |
Conditions - Germline
Condition
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 (1) |
criteria provided, single submitter
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Jun 26, 2014 | RCV000150540.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 5, 2018 | RCV000171832.2 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 1, 2023 | RCV000246903.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2024 | RCV000458560.10 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 8, 2021 | RCV000766863.3 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 16, 2023 | RCV000770552.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 2, 2022 | RCV002478421.1 |
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 05, 2018)
|
criteria provided, single submitter
Method: research
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Cardiomyopathy, arrhythmogenic right ventricular
Affected status: no
Allele origin:
unknown
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Accession: SCV000054851.3
First in ClinVar: Jun 04, 2015 Last updated: Sep 14, 2015 |
Number of individuals with the variant: 1
Secondary finding: yes
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Uncertain significance
(Nov 21, 2018)
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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:
unknown
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000883081.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
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Uncertain significance
(Feb 04, 2016)
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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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000902000.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019 |
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Uncertain significance
(Jun 26, 2014)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000197758.4
First in ClinVar: Jan 30, 2015 Last updated: May 29, 2016 |
Comment:
The Asn493Ser variant in DSG2 has been reported in 1 individual with ARVC (Quart a 2011). It has also been identified in 1/8302 of European … (more)
The Asn493Ser variant in DSG2 has been reported in 1 individual with ARVC (Quart a 2011). It has also been identified in 1/8302 of European American chromosomes and 1/3874 of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS, Andreasen 2013), as well as in 1/1740 Europe an chromosomes by the ClinSeq Project (dbSNP rs375679311, Ng 2013). Computationa l prediction tools and conservation analysis do not provide strong support for o r against an impact to the protein. In summary, the clinical significance of the Asn493Ser variant is uncertain. (less)
Number of individuals with the variant: 1
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001135118.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Jun 08, 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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GeneDx
Accession: SCV000233497.11
First in ClinVar: Jul 05, 2015 Last updated: Sep 23, 2021 |
Comment:
Reported in association with ARVC; however, no additional clinical or segregation information was provided (Quarta et al., 2011); Also reported in an adult female with … (more)
Reported in association with ARVC; however, no additional clinical or segregation information was provided (Quarta et al., 2011); Also reported in an adult female with sinus bradycardia and left atrial abnormality who was evaluated by exome; both sides of her family exhibited cardiac phenotypes, though segregation studies were not reported (Ng et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 163212; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 23861362, 26582918, 21606390, 27535533, 31402444, 31019283, 23299917) (less)
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Likely benign
(Mar 01, 2023)
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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: SCV000320424.7
First in ClinVar: Oct 02, 2016 Last updated: Apr 15, 2023 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Mar 16, 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: SCV001356727.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces asparagine with serine at codon 493 of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces asparagine with serine at codon 493 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 an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606390). This variant has also been identified in 17/280812 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
(Jan 01, 2024)
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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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Invitae
Accession: SCV000551013.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 493 of the DSG2 protein (p.Asn493Ser). … (more)
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 493 of the DSG2 protein (p.Asn493Ser). This variant is present in population databases (rs375679311, gnomAD 0.03%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606390). ClinVar contains an entry for this variant (Variation ID: 163212). 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. 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. (less)
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Uncertain significance
(Feb 02, 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: SCV002776445.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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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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Secondary actionable findings identified by exome sequencing: expected impact on the organisation of care from the study of 700 consecutive tests. | Thauvin-Robinet C | European journal of human genetics : EJHG | 2019 | PMID: 31019283 |
In vitro analysis of arrhythmogenic cardiomyopathy associated desmoglein-2 (DSG2) mutations reveals diverse glycosylation patterns. | Debus JD | Journal of molecular and cellular cardiology | 2019 | PMID: 30885746 |
Interpreting secondary cardiac disease variants in an exome cohort. | Ng D | Circulation. Cardiovascular genetics | 2013 | PMID: 23861362 |
New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. | Andreasen C | European journal of human genetics : EJHG | 2013 | PMID: 23299917 |
Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria. | Quarta G | Circulation | 2011 | PMID: 21606390 |
Text-mined citations for rs375679311 ...
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.