Submissions for variant NM_024422.6(DSC2):c.2603C>T (p.Ser868Phe)

gnomAD frequency: 0.00006  dbSNP: rs141873745

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, University of Leuven	RCV000497924	SCV000579556	uncertain significance	Hypertrophic cardiomyopathy	2017-04-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000520921	SCV000618029	uncertain significance	not provided	2022-12-29	criteria provided, single submitter	clinical testing	Observed in an individual with arrhythmogenic right ventricular cardiomyopathy (Fressart et al., 2010) and in individuals with sudden cardiac death (Nunn et al., 2016; Sanchez et al., 2016; Jaouadi et al., 2020); however, these individuals also harbored variants in other cardiomyopathy-related genes; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30790397, 20400443, 27930701, 26498160, 31970460)
Invitae	RCV000704414	SCV000833363	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2022-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 868 of the DSC2 protein (p.Ser868Phe). This variant is present in population databases (rs141873745, gnomAD 0.01%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy and/or sudden death (PMID: 20400443, 26498160, 27930701, 30790397, 31970460). ClinVar contains an entry for this variant (Variation ID: 427964). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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	RCV001188643	SCV001355729	uncertain significance	Cardiomyopathy	2023-05-02	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 868 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443, 30790397). Both of them also carried a pathogenic truncation variant in the PKP2 gene. This variant has also been reported in three individuals affected with sudden death (PMID: 26498160, 27930701, 31970460) and in an individual affected with dilated cardiomyopathy who carried a pathogenic truncation variant in the TTN gene that could explain the observed phenotype (PMID: 36178741). This variant has been identified in 11/282620 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000520921	SCV001712933	uncertain significance	not provided	2019-12-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002431433	SCV002741347	uncertain significance	Cardiovascular phenotype	2018-11-16	criteria provided, single submitter	clinical testing	The p.S868F variant (also known as c.2603C>T), located in coding exon 16 of the DSC2 gene, results from a C to T substitution at nucleotide position 2603. The serine at codon 868 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant has been detected in an arrhythmogenic right ventricular cardiomyopathy cohort, sudden unexplained death cohorts, and in a hypertrophic cardiomyopathy case; however, clinical details were limited, and other variants in cardiac-related genes were also detected in the reported cases (Nunn LM et al. Europace. 2016;18:888-96; Fressart V et al. Europace. 2010;12:861-8; Sanchez O et al. PLoS ONE. 2016;11:e0167358; Robyns T et al. Eur J Hum Genet. 2017;25(12):1313-1323). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.