Submissions for variant NM_001943.5(DSG2):c.1959G>A (p.Met653Ile)

dbSNP: rs794728088

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181228	SCV000233507	uncertain significance	not provided	2014-06-19	criteria provided, single submitter	clinical testing	p.Met653Ile (ATG>ATA): c.1959 G>A in exon 13 of the DSG2 gene (NM_001943.3). The M653I variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The M653I variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M653I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function, but at least two algorithms concur that this variant is possibly benign. Furthermore, no missense mutations in nearby residues have been reported in association with familial arrhythmia, indicating that this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s).
Color Diagnostics, LLC DBA Color Health	RCV001189660	SCV001356991	uncertain significance	Cardiomyopathy	2023-02-02	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 653 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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	RCV002515305	SCV003015423	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2022-04-10	criteria provided, single submitter	clinical testing	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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 199814). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 653 of the DSG2 protein (p.Met653Ile).
Ambry Genetics	RCV002515306	SCV003572045	uncertain significance	Inborn genetic diseases	2021-08-12	criteria provided, single submitter	clinical testing	The c.1959G>A (p.M653I) alteration is located in exon 13 (coding exon 13) of the DSG2 gene. This alteration results from a G to A substitution at nucleotide position 1959, causing the methionine (M) at amino acid position 653 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.