Submissions for variant NM_024422.6(DSC2):c.854T>C (p.Ile285Thr)

gnomAD frequency: 0.00022  dbSNP: rs199918720

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001078956	SCV000408103	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2018-01-12	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.
Invitae	RCV001078956	SCV000561707	likely benign	Arrhythmogenic right ventricular dysplasia 11	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000521159	SCV000617054	uncertain significance	not provided	2017-01-10	criteria provided, single submitter	clinical testing	The I285T variant of uncertain significance in the DSC2 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in an external variant database. However, the Exome Aggregation Consortium (ExAC) reports I285T was observed in approximately 0.2% of alleles from individuals of European (Finnish) background, indicating it may be a rare variant in this population. Nevertheless, the I285T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the extracellular cadherin 2 domain where only amino acids with similar properties to Isoleucine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000776	SCV001157829	uncertain significance	not specified	2018-09-20	criteria provided, single submitter	clinical testing	The DSC2 c.854T>C; p.Ile285Thr variant (rs199918720), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 326398). This variant is found in the Finnish European population with an overall allele frequency of 0.13% (34/ 25786 alleles) in the Genome Aggregation Database. The isoleucine at codon 285 is moderately conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Ile285Thr variant is uncertain at this time.
Color Diagnostics, LLC DBA Color Health	RCV001183489	SCV001349234	uncertain significance	Cardiomyopathy	2023-06-30	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 285 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 hypertrophic cardiomyopathy (PMID: 25351510) and in individuals suspected of having noncompaction cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy (PMID: 30847666). This variant occurs at an appreciable frequency in the general population and has been identified in 40/282762 chromosomes ((33/25085 Finnish European chromosomes) 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.
Ambry Genetics	RCV002411221	SCV002676205	uncertain significance	Cardiovascular phenotype	2023-02-01	criteria provided, single submitter	clinical testing	The p.I285T variant (also known as c.854T>C), located in coding exon 7 of the DSC2 gene, results from a T to C substitution at nucleotide position 854. The isoleucine at codon 285 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) and cardiomyopathy genetic testing cohorts; however, clinical details were limited and additional cardiac variants were detected in some cases (Lopes LR et al. Heart, 2015 Feb;101:294-301; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is poorly conserved in available 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.
All of Us Research Program, National Institutes of Health	RCV003995852	SCV004816201	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 285 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 hypertrophic cardiomyopathy (PMID: 25351510) and in individuals suspected of having noncompaction cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy (PMID: 30847666). This variant occurs at an appreciable frequency in the general population and has been identified in 40/282762 chromosomes ((33/25085 Finnish European chromosomes) 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000521159	SCV001740777	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000521159	SCV001924705	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000521159	SCV001951666	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000521159	SCV002037683	uncertain significance	not provided		no assertion criteria provided	clinical testing