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

gnomAD frequency: 0.00150  dbSNP: rs121913013

Total submissions: 29

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, Mass General Brigham 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000018311	SCV000287230	likely benign	Arrhythmogenic right ventricular dysplasia 10	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000243248	SCV000318978	likely benign	Cardiovascular phenotype	2018-10-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
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 dysplasia 10	2018-11-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757183	SCV000885319	likely benign	not provided	2022-04-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769508	SCV000900903	likely benign	Cardiomyopathy	2022-02-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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	benign	not provided	2023-08-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000757183	SCV001249535	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	DSG2: BP4
Illumina Laboratory Services, Illumina	RCV000018311	SCV001286847	uncertain significance	Arrhythmogenic right ventricular dysplasia 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 dysplasia 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	2023-08-28	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 8 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. The following publications have been ascertained in the context of this evaluation (PMID: 18382419, 18678517, 17105751, 19039334, 19358943, 20031616, 19955750, 20152563, 20857253, 20716751, 21606390, 20864495, 19569224, 21455723, 20031617, 29038103, 35087879). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=9) and VUS (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
All of Us Research Program, National Institutes of Health	RCV000148471	SCV004819420	likely benign	Arrhythmogenic right ventricular cardiomyopathy	2024-02-05	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000018312	SCV005398500	likely benign	Dilated cardiomyopathy 1BB	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0103 - Loss of function and gain of function are reported mechanisms of disease in this gene and are associated with arrhythmogenic right ventricular dysplasia 10 (ARVD 10; MIM#610193) and dilated cardiomyopathy 1BB (DCM; MIM#612877) (ClinVar, PMID: 23071725). (I) 0108 - This gene is associated with both recessive and dominant disease. It is commonly associated to dominant inheritance, however recessive has been reported in severe DCM patients (OMIM). (I) 0112 - The ARVD condition associated with this gene has incomplete penetrance (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of dilated cardiomyopathy 1BB (MIM#612877). (SB) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2, v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated cadherin 1 domain (Uniprot). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported many times as both a VUS, but more recently and commonly as likely benign (ClinVar, LOVD, PMID: 28087566, PMID: 32268277, PMID: 28472724). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000018311	SCV000038590	pathogenic	Arrhythmogenic right ventricular dysplasia 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 1	2014-07-23	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000757183	SCV001740318	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000037270	SCV001919801	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000757183	SCV001926490	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000757183	SCV001952192	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000757183	SCV001972044	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944829	SCV004764159	likely benign	DSG2-related disorder	2021-02-03	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).