Submissions for variant NM_001943.5(DSG2):c.1072G>A (p.Ala358Thr)

gnomAD frequency: 0.00001  dbSNP: rs758537946

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181214	SCV000233492	uncertain significance	not provided	2018-06-15	criteria provided, single submitter	clinical testing	p.Ala358Thr (A358T) GCA>ACA: c.1072 G>A in exon 9 of the DSG2 gene (NM_001943.3). The Ala358Thr variant in the DSG2 gene has been reported with unclear significance in association with ARVC (Kapplinger J et al., 2011; Cox M et al., 2011). Kapplinger et al reported Ala358Thr in a patient with ARVC who harbored a large gene deletion in the PKP2 gene and another missense variant in the TMEM43 gene. Also, Cox et al. reported Ala358Thr as an unclassified variant when it was identified in their cohort of patient with ARVC. Ala358Thr results in a non-conservative amino acid substitution of a non-polar Alanine with a polar Threonine at a position that is conserved across species. In silico analysis predicts Ala358Thr is damaging to the protein structure/function. The Ala358Thr 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. With the information available at this time, we cannot definitively determine if Ala358Thr is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s).
Invitae	RCV000537458	SCV000641958	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2022-12-10	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. 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 DSG2 protein function. ClinVar contains an entry for this variant (Variation ID: 199805). This missense change has been observed in individual(s) with arrhythmogenic cardiomyopathy (PMID: 21636032, 25820315). This variant is present in population databases (rs758537946, gnomAD 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 358 of the DSG2 protein (p.Ala358Thr).
Illumina Laboratory Services, Illumina	RCV000537458	SCV001283484	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV001178633	SCV001343132	uncertain significance	Cardiomyopathy	2023-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 358 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 four unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 21636032, 25820315, 34998950). One of these individuals also carried a pathogenic variant in the PKP2 gene (PMID: 25820315). This variant has also been reported in an invividual affected with sudden unexplained death (PMID: 29016939). This variant has been identified in 2/249360 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.
Ambry Genetics	RCV003165382	SCV003858296	uncertain significance	Cardiovascular phenotype	2022-12-14	criteria provided, single submitter	clinical testing	The p.A358T variant (also known as c.1072G>A), located in coding exon 9 of the DSG2 gene, results from a G to A substitution at nucleotide position 1072. The alanine at codon 358 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts; however, clinical details were limited and additional alterations in other ARVC-related genes were identified (Cox MG et al. Circulation, 2011 Jun;123:2690-700; Groeneweg JA et al. Circ Cardiovasc Genet, 2015 Jun;8:437-46; Hellenthal N et al. Europace, 2017 Nov;19:1881-1890). This amino acid position is highly 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.
Blueprint Genetics	RCV000208418	SCV000263853	likely pathogenic	Primary dilated cardiomyopathy	2015-09-15	flagged submission	clinical testing