Submissions for variant NM_024422.6(DSC2):c.266C>T (p.Ser89Leu)

gnomAD frequency: 0.00006  dbSNP: rs141379407

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000555831	SCV000645013	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 89 of the DSC2 protein (p.Ser89Leu). This variant is present in population databases (rs141379407, gnomAD 0.03%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 21859740). ClinVar contains an entry for this variant (Variation ID: 468381). 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	RCV001177887	SCV001342186	uncertain significance	Cardiomyopathy	2023-06-30	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 89 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 dilated cardiomyopathy (PMID: 21859740), an individual affected with hypertrophic cardiomyopathy (PMID: 25351510), an infant who died of sudden infant death syndrome (PMID: 27435932), and an individual suspected of having dilated cardiomyopathy (PMID: 30847666). This variant has been identified in 24/282254 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.
GeneDx	RCV001591243	SCV001815177	uncertain significance	not provided	2021-06-18	criteria provided, single submitter	clinical testing	Has been reported in an individual with dilated cardiomyopathy (Garcia-Pavia et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 468381; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918, 27535533, 21859740)
Ambry Genetics	RCV002431640	SCV002741291	uncertain significance	Cardiovascular phenotype	2021-04-23	criteria provided, single submitter	clinical testing	The p.S89L variant (also known as c.266C>T), located in coding exon 3 of the DSC2 gene, results from a C to T substitution at nucleotide position 266. The serine at codon 89 is replaced by leucine, an amino acid with dissimilar properties. This variant has been detected in individuals from cohorts with hypertrophic and dilated cardiomyopathy; however, clinical details were limited and, in some cases, additional variants in cardiac-related genes were also detected (Garcia-Pavia P et al. Heart, 2011 Nov;97:1744-52; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Lopes LR et al. J Med Genet, 2013 Apr;50:228-39). This amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000555831	SCV002775482	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-08-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999354	SCV004819364	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 89 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 dilated cardiomyopathy (PMID: 21859740), an individual affected with hypertrophic cardiomyopathy (PMID: 25351510), an infant who died of sudden infant death syndrome (PMID: 27435932), and an individual suspected of having dilated cardiomyopathy (PMID: 30847666). This variant has been identified in 24/282254 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.