Submissions for variant NM_024422.6(DSC2):c.1766T>C (p.Met589Thr)

gnomAD frequency: 0.00016  dbSNP: rs201856473

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000467720	SCV000551484	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 589 of the DSC2 protein (p.Met589Thr). This variant is present in population databases (rs201856473, gnomAD 0.01%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 410648). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSC2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000481832	SCV000564947	uncertain significance	not provided	2023-08-21	criteria provided, single submitter	clinical testing	Reported in published literature in a patient referred for arrhythmogenic right ventricular cardiomyopathy (ARVC) genetic testing and in a patient with monomorphic and polymorphic ventricular tachycardia who harbored additional cardiogenetic variants (Walsh et al., 2017; Chen et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31402444, 35474678, 27532257)
Phosphorus, Inc.	RCV000467720	SCV000679937	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2017-08-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619775	SCV000734886	likely benign	Cardiovascular phenotype	2023-03-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000772020	SCV000904976	uncertain significance	Cardiomyopathy	2022-12-20	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 589 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257). This variant has been identified in 20/282460 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000467720	SCV002792893	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-07-22	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000467720	SCV003925310	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2022-01-28	criteria provided, single submitter	clinical testing	The c.1766T>C p.(Met589Thr) missense variant identified in the DSC2 gene has 0.0001643 allele frequency in the gnomAD(v3) database (25 out of 152178 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in that database. The variant affects a conserved residue and is predicted benign by multiple in silico prediction tools (CADD score = 18.05, REVEL score = 0.064). This variant has been eported in the ClinVar database as a variant of uncertain significance [Variation ID: 410648] ) and has been reported in one affected individual in the literature with arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257). Based on the available evidence, the c.1766T>C p.(Met589Thr) variant identified in the DSC2 gene is reported as a Variant of Uncertain Significance.