Submissions for variant NM_024422.6(DSC2):c.1721G>A (p.Ser574Asn)

gnomAD frequency: 0.00010  dbSNP: rs150318400

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154699	SCV000204378	uncertain significance	not specified	2014-05-01	criteria provided, single submitter	clinical testing	The Ser574Asn variant in DSC2 has been reported in 1 individual with ARVC (Quart a 2011). It has also been identified in 4/8600 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1 50318400). Serine (Ser) at position 574 is not conserved evolution, raising the possibility that a change at this position may be tolerated. In summary, the cli nical significance of the Ser574Asn variant is uncertain.
GeneDx	RCV000588984	SCV000233431	uncertain significance	not provided	2021-09-10	criteria provided, single submitter	clinical testing	Reported in association with arrhythmogenic right ventricular dysplasia (ARVC) and dilated cardiomyopathy (DCM) (Quarta et al., 2011; van Lint et al., 2019; Verdonschot et al., 2020), as well as in a woman with "probable" ARVC whose child was a victim of sudden unexplained death (van der Werf et al., 2010); however, additional clinical and segregation data were not provided; In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 178018; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 23299917, 20646679, 21606390, 31402444, 30847666, 32880476)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154699	SCV000699495	likely benign	not specified	2024-11-29	criteria provided, single submitter	clinical testing	Variant summary: DSC2 c.1721G>A (p.Ser574Asn) results in a conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251034 control chromosomes, predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Cardiomyopathy phenotype (2.5e-05). c.1721G>A has been reported in the literature in individuals affected with DSC2-related conditions (examples: van der Werf_2010, van Lint_2019, Verdonschot_2020) . These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrence with another pathogenic variant has been reported (KCNQ1 c.1781G>A, p.R594Q), providing supporting evidence for a benign role (Internal sample). The following publications have been ascertained in the context of this evaluation (PMID: 21606390, 23299917, 20646679, 30847666, 31402444, 32880476, 38689299).ClinVar contains an entry for this variant (Variation ID: 178018). Based on the evidence outlined above, the variant was classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001068652	SCV001233777	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 574 of the DSC2 protein (p.Ser574Asn). This variant is present in population databases (rs150318400, gnomAD 0.01%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular dyplasia/cardiomyopathy, dilated cardiomyopathy, and/or unspecified cardiomyopathy (PMID: 20646679, 21606390, 30847666, 32880476, 37937776). ClinVar contains an entry for this variant (Variation ID: 178018). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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	RCV001178119	SCV001342475	uncertain significance	Cardiomyopathy	2022-12-02	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 574 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: 21606390). This variant has also been identified in 17/282410 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588984	SCV001471564	uncertain significance	not provided	2020-07-24	criteria provided, single submitter	clinical testing	The DSC2 c.1721G>A; p.Ser574Asn variant (rs150318400) is reported in the literature in an individual affected with arrhythmogenic right ventricular cardiomyopathy (ARVC) and in the parent of a child with sudden unexpected death and suspected ARVC (Quarta 2011, van der Werf 2010). This variant is found in the non-Finnish European population with an overall allele frequency of 0.01% (16/128894 alleles) in the Genome Aggregation Database. The serine at codon 574 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Ser574Asn variant is uncertain at this time. References: Quarta et al. Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria. Circulation. 2011;123(23):2701-2709. van der Werf C et al. Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the young: the experience of a tertiary referral center in The Netherlands. Heart Rhythm. 2010;7(10):1383-1389.
Ambry Genetics	RCV002399542	SCV002713642	likely benign	Cardiovascular phenotype	2021-06-11	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.
All of Us Research Program, National Institutes of Health	RCV003998259	SCV004816129	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2023-12-15	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 574 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 individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606390). This variant has also been identified in 17/282410 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.