Submissions for variant NM_024422.6(DSC2):c.1018A>G (p.Thr340Ala)

gnomAD frequency: 0.00003  dbSNP: rs368299411

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000990080	SCV001140867	benign	Arrhythmogenic right ventricular dysplasia 11	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001183304	SCV001348999	uncertain significance	Cardiomyopathy	2023-06-07	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 340 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 suspected of having arrhythmogenic right ventricular cardiomyopathy, who also carried a pathogenic truncation variant in the PKP2 gene (PMID: 19863551), and in another individual affected with dilated cardiomyopathy (PMID: 25163546). This variant has been identified in 9/282402 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256829	SCV001433310	uncertain significance	Arrhythmogenic right ventricular dysplasia 1	2019-12-10	criteria provided, single submitter	clinical testing
GeneDx	RCV001582617	SCV001811608	uncertain significance	not provided	2019-10-21	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in association with suspected ARVC and DCM (Barahona-Dussault et al., 2010; Haas et al., 2015); This variant is associated with the following publications: (PMID: 31402444, 25163546, 19863551, 25637381, 23299917)
Ambry Genetics	RCV002354337	SCV002653063	likely benign	Cardiovascular phenotype	2021-09-17	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	RCV000990080	SCV003255214	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 340 of the DSC2 protein (p.Thr340Ala). This variant is present in population databases (rs368299411, gnomAD 0.006%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy/dysplasia (PMID: 19863551). ClinVar contains an entry for this variant (Variation ID: 161222). 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.
All of Us Research Program, National Institutes of Health	RCV000148466	SCV004816186	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 340 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 suspected of having arrhythmogenic right ventricular cardiomyopathy, who also carried a pathogenic truncation variant in the PKP2 gene (PMID: 19863551), and in another individual affected with dilated cardiomyopathy (PMID: 25163546). This variant has been identified in 9/282402 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.
CSER _CC_NCGL, University of Washington	RCV000148466	SCV000190166	likely benign	Familial isolated arrhythmogenic right ventricular dysplasia	2014-06-01	no assertion criteria provided	research