Submissions for variant NM_024422.6(DSC2):c.802A>G (p.Thr268Ala)

gnomAD frequency: 0.00003  dbSNP: rs201015785

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154700	SCV000204379	likely benign	not specified	2019-10-18	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000656842	SCV000233420	uncertain significance	not provided	2022-05-28	criteria provided, single submitter	clinical testing	Reported in two pediatric patients with DCM, though both harbored additional disease-related variants; also reported in an adult patient with DCM, though this individual harbored a nonsense variant in the TTN gene (Kuhnisch et al., 2019; Burstein et al., 2021; Pena-Pena et al., 2021); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 34426522, 32746448, 32826072, 31568572)
Ambry Genetics	RCV000252152	SCV000318264	likely benign	Cardiovascular phenotype	2021-07-16	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.
Invitae	RCV000466138	SCV000551495	likely benign	Arrhythmogenic right ventricular dysplasia 11	2023-12-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000777997	SCV000914104	uncertain significance	Cardiomyopathy	2023-04-11	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 268 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 individuals affected with dilated cardiomyopathy (PMID: 31568572, 32746448, 32826072), cardiomyopathy (PMID: 32746448), long QT syndrome (PMID: 35703482), and in six individuals suspected of having hypertrophic cardiomyopathy (PMID: 30847666). This variant has also been identified in 39/282652 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	RCV000466138	SCV001282908	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000466138	SCV001367678	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2020-03-17	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3.
Revvity Omics, Revvity	RCV000466138	SCV003829120	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2020-02-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154700	SCV004038776	likely benign	not specified	2023-08-21	criteria provided, single submitter	clinical testing	Variant summary: DSC2 c.802A>G (p.Thr268Ala) results in a non-conservative amino acid change located in the Cadherin-like (IPR002126) of 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 0.00015 in 251258 control chromosomes (gnomAD). The observed variant frequency is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.802A>G has been reported in the literature in individuals affected with Cardiomyopathy or Long QT Syndrome without strong evidence of causality (Burstein_2021, Kuhnisch_2019, Pena-Pena_2021, Pottinger_2020, Saat_2022), and some patients were repoted to have other co-occurring variants, including a truncating TTN variant. These reports 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. The following publications have been ascertained in the context of this evaluation (PMID: 32826072, 32009526, 31568572, 32746448, 35703482). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=5) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777997	SCV004240495	uncertain significance	Cardiomyopathy	2023-01-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998260	SCV004816206	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 268 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 two unrelated individuals affected with dilated cardiomyopathy (PMID: 31568572, 32746448), in another individual affected with cardiomyopathy (PMID: 32746448), and in six individuals suspected of having hypertrophic cardiomyopathy (PMID: 30847666). This variant has also been identified in 39/282652 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.