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NM_001943.5(DSG2):c.2434G>T (p.Gly812Cys)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(1);Uncertain significance(3)

Review status:
criteria provided, conflicting interpretations
Submissions:
6 (Most recent: Jan 7, 2021)
Last evaluated:
Oct 30, 2020
Accession:
VCV000016814.8
Variation ID:
16814
Description:
single nucleotide variant
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NM_001943.5(DSG2):c.2434G>T (p.Gly812Cys)

Allele ID
31853
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
18q12.1
Genomic location
18: 31545820 (GRCh38) GRCh38 UCSC
18: 29125783 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
Q14126:p.Gly812Cys
NC_000018.10:g.31545820G>T
NC_000018.9:g.29125783G>T
... more HGVS
Protein change
G812C
Other names
-
Canonical SPDI
NC_000018.10:31545819:G:T
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Links
ClinGen: CA021794
UniProtKB: Q14126#VAR_029368
OMIM: 125671.0005
dbSNP: rs121913010
VarSome
Comment on variant
NCBI staff reviewed the sequence information reported in PubMed 16773573 to determine the location of this allele on current reference sequence.
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 2 criteria provided, single submitter Oct 30, 2020 RCV000018307.30
Likely pathogenic 1 criteria provided, single submitter Jul 9, 2018 RCV000618751.1
Uncertain significance 1 criteria provided, single submitter Mar 25, 2020 RCV001183802.1
Uncertain significance 1 criteria provided, single submitter Sep 3, 2019 RCV001195104.1
Likely pathogenic 1 no assertion criteria provided Jun 1, 2014 RCV000037286.5
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
DSG2 Little evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
638 1094
DSG2-AS1 - - - GRCh38 - 435

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Sep 03, 2019)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine
Accession: SCV000060943.5
Submitted: (Jun 03, 2020)
Evidence details
Publications
PubMed (5)
Comment:
The p.Gly812Cys variant in DSG2 has been identified in at least 2 individuals with ARVC (Awad 2006, Ambry pers. comm., LMM data). It has also … (more)
Uncertain significance
(Mar 25, 2020)
criteria provided, single submitter
Method: clinical testing
Cardiomyopathy
Allele origin: germline
Color Health, Inc
Accession: SCV001349629.1
Submitted: (May 19, 2020)
Comment:
This missense variant replaces glycine with cysteine at codon 812 of the DSG2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
Evidence details
Likely pathogenic
(Jul 09, 2018)
criteria provided, single submitter
Method: clinical testing
Cardiovascular phenotype
Allele origin: germline
Ambry Genetics
Accession: SCV000737925.3
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (6)
Comment:
The p.G812C variant (also known as c.2434G>T), located in coding exon 15 of the DSG2 gene, results from a G to T substitution at nucleotide … (more)
Uncertain significance
(Oct 30, 2020)
criteria provided, single submitter
Method: clinical testing
Arrhythmogenic right ventricular cardiomyopathy, type 10
Allele origin: germline
Invitae
Accession: SCV001214221.2
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (3)
Comment:
This sequence change replaces glycine with cysteine at codon 812 of the DSG2 protein (p.Gly812Cys). The glycine residue is highly conserved and there is a … (more)
Pathogenic
(Jul 01, 2006)
no assertion criteria provided
Method: literature only
ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 10
Allele origin: germline
OMIM
Accession: SCV000038586.3
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (1)
Likely pathogenic
(Jun 01, 2014)
no assertion criteria provided
Method: research
Cardiomyopathy, arrhythmogenic right ventricular
(Autosomal dominant inheritance)
Allele origin: germline
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190171.1
Submitted: (Aug 28, 2014)
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
Evidence details

Functional evidence

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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 this variant

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Title Author Journal Year Link
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Amendola LM Genome research 2015 PMID: 25637381
Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function. Schlipp A Cardiovascular research 2014 PMID: 25213555
Actionable, pathogenic incidental findings in 1,000 participants' exomes. Dorschner MO American journal of human genetics 2013 PMID: 24055113
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
Shared desmosome gene findings in early and late onset arrhythmogenic right ventricular dysplasia/cardiomyopathy. Tan BY Journal of cardiovascular translational research 2010 PMID: 20857253
Novel missense mutations in exon 15 of desmoglein-2: role of the intracellular cadherin segment in arrhythmogenic right ventricular cardiomyopathy? Gehmlich K Heart rhythm 2010 PMID: 20708101
Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy. den Haan AD Circulation. Cardiovascular genetics 2009 PMID: 20031617
Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Awad MM Nature clinical practice. Cardiovascular medicine 2008 PMID: 18382419
DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy. Awad MM American journal of human genetics 2006 PMID: 16773573

Text-mined citations for rs121913010...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2021