Submissions for variant NM_024422.6(DSC2):c.1073C>T (p.Thr358Ile)

gnomAD frequency: 0.00104  dbSNP: rs139399951

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172527	SCV000051522	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039400	SCV000063084	likely benign	not specified	2017-09-04	criteria provided, single submitter	clinical testing	p.Thr358Ile in exon 8 of DSC2: This variant is not expected to have clinical sig nificance because it has been identified in 0.37% (94/25778) of Finnish chromoso mes, including 3 homozygotes, by the Genome Aggregation Database (gnomAD, http:/ /gnomAD.broadinstitute.org; dbSNP rs139399951).
CSER _CC_NCGL, University of Washington	RCV000210891	SCV000264600	likely benign	Arrhythmogenic right ventricular cardiomyopathy	2015-12-01	criteria provided, single submitter	research
Invitae	RCV000228131	SCV000290726	likely benign	Arrhythmogenic right ventricular dysplasia 11	2024-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000243453	SCV000319164	likely benign	Cardiovascular phenotype	2018-03-23	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.
GeneDx	RCV000172527	SCV000516119	likely benign	not provided	2021-02-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24704780, 18678517, 25351510, 27153395)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000172527	SCV000610746	likely benign	not provided	2017-03-10	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000228131	SCV000743494	likely benign	Arrhythmogenic right ventricular dysplasia 11	2017-03-17	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000228131	SCV000744764	likely benign	Arrhythmogenic right ventricular dysplasia 11	2017-06-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770540	SCV000901987	benign	Cardiomyopathy	2016-11-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770540	SCV000903367	likely benign	Cardiomyopathy	2018-03-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000228131	SCV001281727	likely benign	Arrhythmogenic right ventricular dysplasia 11	2017-04-27	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039400	SCV001442580	benign	not specified	2020-10-26	criteria provided, single submitter	clinical testing	Variant summary: DSC2 c.1073C>T (p.Thr358Ile) 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 0.0013 in 250956 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 8-fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00016), strongly suggesting that the variant is benign. c.1073C>T has been reported in the literature in an individual with a possible diagnosis of arrhythmogenic cardiomyopathy (AC), however, two first-degree relatives carrying the variant, were unaffected, and there was no family history of AC (Rasmussen_2014). These authors also reported that patient derived keratinocytes expressed normal amount of the DSC2 protein, however, this does not allow conclusions about the variant effect on protein function (Rasmussen_2014). 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Fulgent Genetics, Fulgent Genetics	RCV000228131	SCV002811789	likely benign	Arrhythmogenic right ventricular dysplasia 11	2022-04-28	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000157171	SCV000206895	likely benign	Cardiac arrest	2014-08-26	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000039400	SCV001922235	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000039400	SCV001955304	benign	not specified		no assertion criteria provided	clinical testing