ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1072G>A (p.Ala358Thr) (rs758537946)

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Total submissions: 5
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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).
Blueprint Genetics RCV000208418 SCV000263853 likely pathogenic Primary dilated cardiomyopathy 2015-09-15 criteria provided, single submitter clinical testing
Invitae RCV000537458 SCV000641958 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-08-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 358 of the DSG2 protein (p.Ala358Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs758537946, ExAC 0.003%). This variant has been reported in several individuals affected with arrhythmogenic cardiomyopathy (PMID: 21636032, 25820315). However, in one of those individuals, a pathogenic allele was also identified in PKP2 which suggests that this c.1072G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 199805). 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV000537458 SCV001283484 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 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 Health, Inc RCV001178633 SCV001343132 uncertain significance Cardiomyopathy 2018-12-19 criteria provided, single submitter clinical testing

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