Submissions for variant NM_001943.5(DSG2):c.3209C>T (p.Thr1070Met)

gnomAD frequency: 0.00223  dbSNP: rs149617776

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172531	SCV000054852	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154705	SCV000204384	likely benign	not specified	2014-06-30	criteria provided, single submitter	clinical testing	Thr1070Met in exon 15 of DSG2: This variant is not expected to have clinical sig nificance because it is not conserved across species, including mammals. Of note , >15 mammals have a methionine (Met) at this position. In addition, computation al prediction tools do not suggest a high likelihood of impact to the protein. I t has also been identified in 5/8274 of European American chromosomes and by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1496 17776).
Invitae	RCV001079476	SCV000287241	benign	Arrhythmogenic right ventricular dysplasia 10	2024-01-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001079476	SCV000408265	likely benign	Arrhythmogenic right ventricular dysplasia 10	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000172531	SCV000609787	likely benign	not provided	2017-03-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000154705	SCV000703280	benign	not specified	2016-11-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621371	SCV000737580	benign	Cardiovascular phenotype	2016-10-20	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Color Diagnostics, LLC DBA Color Health	RCV000771264	SCV000903382	benign	Cardiomyopathy	2018-05-11	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000172531	SCV000987418	benign	not provided		criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771264	SCV001332957	benign	Cardiomyopathy	2018-07-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154705	SCV001362563	benign	not specified	2019-01-21	criteria provided, single submitter	clinical testing	Variant summary: DSG2 c.3209C>T (p.Thr1070Met) results in a non-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 0.0017 in 277006 control chromosomes, predominantly at a frequency of 0.0087 within the Latino subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 348 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.3209C>T has been reported in the literature among 870 participants not selected for arrhythmia, cardiomyopathy (Ng_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant predomiantly as likely benign/benign (4x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000172531	SCV001893804	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30821013, 26230511)
Fulgent Genetics, Fulgent Genetics	RCV002492583	SCV002797344	likely benign	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2022-05-25	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172531	SCV001741493	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000172531	SCV001922883	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172531	SCV001928354	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172531	SCV001970471	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172531	SCV001979622	likely benign	not provided		no assertion criteria provided	clinical testing