ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1174G>A (p.Val392Ile) (rs193922639)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000148472 SCV000051376 likely benign Arrhythmogenic right ventricular cardiomyopathy 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037262 SCV000060919 likely benign not specified 2015-04-03 criteria provided, single submitter clinical testing p.Val392Ile in exon 9 of DSG2: This variant has been reported in many individual s with diverse presentations (ARVC, LQTS1, LDAC, DCM: Syrris 2007, Bhuiyan 2009, Bauce 2010, Klauke 2010, Quarta 2011, Cox 2011, Bauce 2011, Garcia-Parva 2011, LMM unpublished data). However, this variant has also been identified in 0.7% (1 11/16510) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC,;dbSNP rs193922639). In addition, valine (Val) at position 392 is poorly conserved in evolution and the variant is present in two species (including 1 mammal), suggesting that a change to this position may be t olerated. In summary, this variant is likely benign but a modifying role cannot be excluded.
CSER _CC_NCGL, University of Washington RCV000148472 SCV000190173 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx RCV000037262 SCV000233494 likely benign not specified 2017-06-08 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.
Invitae RCV001081298 SCV000561397 benign Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-12-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037262 SCV000697880 benign not specified 2019-08-26 criteria provided, single submitter clinical testing Variant summary: DSG2 c.1174G>A (p.Val392Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 249420 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 200 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. Though c.1174G>A has been reported in the literature in individuals affected with ARVC/D, LQTS and DCM, including families showing incomplete co-segregation with disease, in addition, multiple co-occurrences with other pathogenic variants have been noted (PKP2 c.148_151delACAG (p.Thr50fsX61), Bauce_2010, Rigato_2013; PKP2 c.235C>T (p.Arg79X), Cox _2011), providing supporting evidence for a benign role. Publication also reported experimental evidence evaluating an impact on protein function, and demonstrated no damaging effect of this variant (Gaertner_2012, Dieding_2017). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as Benign (2x), Likely benign (3x) or VUS (1x). Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics RCV000619528 SCV000734934 likely benign Cardiovascular phenotype 2018-06-08 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000029667 SCV000901998 benign Cardiomyopathy 2018-07-25 criteria provided, single submitter clinical testing
Color Health, Inc RCV000029667 SCV000902997 benign Cardiomyopathy 2018-06-11 criteria provided, single submitter clinical testing
Mendelics RCV000472660 SCV001135117 uncertain significance not provided 2019-05-28 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256759 SCV001433191 benign Arrhythmogenic right ventricular dysplasia, familial 1 2019-07-25 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287832 SCV001474568 likely benign none provided 2020-04-08 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000472660 SCV001739689 likely benign not provided no assertion criteria provided clinical testing

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