Submissions for variant NM_001943.5(DSG2):c.3044T>C (p.Met1015Thr)

gnomAD frequency: 0.00001  dbSNP: rs886053716

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000393794	SCV000408261	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	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.
GeneDx	RCV000521532	SCV000617003	uncertain significance	not provided	2017-10-19	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the DSG2 gene. The M1015T variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The M1015T 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. However, this substitution occurs at a position where amino acids with similar properties to methionine (M) are tolerated across species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Color Diagnostics, LLC DBA Color Health	RCV001181528	SCV001346700	uncertain significance	Cardiomyopathy	2023-08-10	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 1015 of the DSG2 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 one individual affected with dilated cardiomyopathy (PMID: 32880476). This variant has been identified in 2/249416 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.
Invitae	RCV000393794	SCV001421853	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2022-03-27	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 326489). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32880476). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1015 of the DSG2 protein (p.Met1015Thr).
Ambry Genetics	RCV002446587	SCV002754092	uncertain significance	Cardiovascular phenotype	2018-10-02	criteria provided, single submitter	clinical testing	The p.M1015T variant (also known as c.3044T>C), located in coding exon 15 of the DSG2 gene, results from a T to C substitution at nucleotide position 3044. The methionine at codon 1015 is replaced by threonine, an amino acid with similar properties. This amino acid position is well 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.