Submissions for variant NM_024422.6(DSC2):c.327A>G (p.Ile109Met)

gnomAD frequency: 0.00001  dbSNP: rs373305929

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039433	SCV000063117	likely benign	not specified	2017-01-20	criteria provided, single submitter	clinical testing	p.Ile109Met in exon 3 of DSC2: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, 5 mammals (Alpaca, Horse, Bat, Microbat and Elephant) have a methionine (Met ) at this position. Of note, this variant has been reported by our laboratory in 1 Asian individual with ARVC (LMM data, Palmisano 2011), however, this individu al carried an additional variant likely to explain disease (c.2489+1G>A in PKP2) . This p.Ile109Met has also been reported in ClinVar (Variation ID:46190). Final ly, it has also been identified in 1/16454 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs373305929) .
GeneDx	RCV000766855	SCV000233413	uncertain significance	not provided	2020-05-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21822014, 23299917, 26220970)
Invitae	RCV000625301	SCV000766335	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 109 of the DSC2 protein (p.Ile109Met). This variant is present in population databases (rs373305929, gnomAD 0.005%). This missense change has been observed in individual(s) with Brugada syndrome and arrhythmogenic right ventricular cardiomyopathy, as well as unaffected individuals (PMID: 21822014, 26220970). ClinVar contains an entry for this variant (Variation ID: 46190). 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.
Color Diagnostics, LLC DBA Color Health	RCV000777975	SCV000914080	uncertain significance	Cardiomyopathy	2023-01-27	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 109 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 performed for this variant. This variant has been observed in an individual with arrhythmogenic right ventricular cardiomyopathy, as well as in the affected father (PMID: 21822014). However, these individuals also carried a pathogenic splice variant in PKP2, suggesting that this missense variant may not be the primary cause of disease in this family. This variant has been identified in 9/250756 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.
Illumina Laboratory Services, Illumina	RCV000625301	SCV001285907	uncertain significance	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039433	SCV001519555	uncertain significance	not specified	2021-03-15	criteria provided, single submitter	clinical testing	Variant summary: DSC2 c.327A>G (p.Ile109Met) results in a conservative amino acid change located in the Cadherin prodomain of 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 3.6e-05 in 250756 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.327A>G has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia or Brugada syndrome (Palmisano_2011, DiResta_2015). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. Co-occurrence with a pathogenic variant has been reported (PKP2 c.2489+1G>A), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS n=5, likely benign n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002321517	SCV002606878	likely benign	Cardiovascular phenotype	2022-02-23	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777975	SCV003838779	uncertain significance	Cardiomyopathy	2021-10-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996444	SCV004819357	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 109 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 performed for this variant. This variant has been observed in an individual with arrhythmogenic right ventricular cardiomyopathy, as well as in the affected father (PMID: 21822014). However, these individuals also carried a pathogenic splice variant in PKP2, suggesting that this missense variant may not be the primary cause of disease in this family. This variant has been identified in 9/250756 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.