ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.166G>A (p.Val56Met) (rs121913013)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 21
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000148471 SCV000051377 likely benign Arrhythmogenic right ventricular cardiomyopathy 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037270 SCV000060927 likely benign not specified 2015-03-18 criteria provided, single submitter clinical testing p.Val56Met in exon 3 of DSG2: This variant has been reported in at least 4 indiv iduals with ARVC and was initially believed to be pathogenic (Syrris 2007, Bhuiy an 2009, Den Haan 2009, Christensen 2010, Quarta 2011). However, it has been ide ntified in 0.3% (185/66660) of European chromosomes (including 1 homozygous indi vidual) by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs121913013), strongly arguing against a disease causing role when pres ent in isolation. There is some evidence that the p.Val56Met variant may predisp ose to dilated cardiomyopathy as Posch 2008 detected it in 13/538 DCM probands v ersus 3/617 control individuals (p<0.007), but this study has not been replicate d nor firmly established. In summary, the p.Val56Met variant is unlikely to be d isease causing in isolation, but its increased frequency in patients with DCM ve rsus healthy controls raises the possibility that it acts as a modifier when pre sent together with other variants.
GeneDx RCV000037270 SCV000233478 likely benign not specified 2017-10-25 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 RCV000018311 SCV000287230 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-11-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000243248 SCV000318978 likely benign Cardiovascular phenotype 2018-10-29 criteria provided, single submitter clinical testing Other strong data supporting benign classification;Subpopulation frequency in support of benign classification
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000037270 SCV000747976 uncertain significance not specified 2017-01-30 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000018311 SCV000883079 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 10 2018-11-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000037270 SCV000885319 likely benign not specified 2019-04-16 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769508 SCV000900903 likely benign Cardiomyopathy 2017-07-17 criteria provided, single submitter clinical testing
Color Health, Inc RCV000769508 SCV000910818 likely benign Cardiomyopathy 2018-04-08 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852739 SCV000995454 likely benign Long QT syndrome 2018-02-11 criteria provided, single submitter clinical testing
Mendelics RCV000757183 SCV001135116 uncertain significance not provided 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000757183 SCV001249535 uncertain significance not provided 2019-11-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000018311 SCV001286847 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2018-01-19 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center RCV000018311 SCV001428597 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2017-07-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037270 SCV001737740 likely benign not specified 2021-06-14 criteria provided, single submitter clinical testing Variant summary: DSG2 c.166G>A (p.Val56Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 253524 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 7.56 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00025), strongly suggesting that the variant is benign. c.166G>A has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and DCM (Syrris_2007, Posch_2008, Christensen_2010, Dalal_2009, Bhuyian_2009, Quarta_2011). However, the high presence of the variant in the general population and in controls suggests against a disease causing role for this variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 14 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Nine labs classify the variant as likely benign while five classify the variant as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
OMIM RCV000018311 SCV000038590 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2008-09-01 no assertion criteria provided literature only
OMIM RCV000018312 SCV000038591 risk factor Dilated cardiomyopathy 1BB 2008-09-01 no assertion criteria provided literature only
CSER _CC_NCGL, University of Washington RCV000148471 SCV000190172 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2014-06-01 no assertion criteria provided research
Blueprint Genetics RCV000157179 SCV000206903 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-07-23 no assertion criteria provided clinical testing
Blueprint Genetics RCV000157180 SCV000206904 uncertain significance Catecholaminergic polymorphic ventricular tachycardia type 1 2014-07-23 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.