ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.6G>A (p.Ala2=) (rs368809971)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000154701 SCV000168251 benign not specified 2013-10-03 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154701 SCV000204380 likely benign not specified 2013-04-20 criteria provided, single submitter clinical testing Ala2Ala in exon 1 of DSG2: This variant is not expected to have clinical signifi cance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.2% (14/7372) of Europ ean American chromosomes from a broad population by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS). Ala2Ala in exon 1 of DSG2 (allele fr equency = 0.2%, 14/7372) **
Ambry Genetics RCV000245313 SCV000319940 likely benign Cardiovascular phenotype 2015-07-09 criteria provided, single submitter clinical testing Synonymous alterations with insufficient evidence to classify as benign
Illumina Clinical Services Laboratory,Illumina RCV001080998 SCV000408191 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 10 2018-03-19 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae RCV001080998 SCV000561392 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-12-08 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757184 SCV000885321 benign not provided 2018-06-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000776121 SCV000911003 benign Cardiomyopathy 2018-08-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000154701 SCV000917287 benign not specified 2018-05-08 criteria provided, single submitter clinical testing Variant summary: DSG2 c.6G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0051 in 45050 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 500 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. c.6G>A has been reported in the literature in an individual affected with Arrhythmia (Lahtinen 2011). This report however does not provide unequivocal conclusions about association of the variant with Arrhythmia. Co-occurrence with another pathogenic variant have been found in our internal database (KCNH2 c.1841C>T, p.Ala614Val), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (three of them calling it 'likely benign' and one classifying it as a 'VUS') without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000757184 SCV001742347 likely benign not provided no assertion criteria provided clinical testing

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