ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1063G>A (p.Ala355Thr) (rs201046640)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171900 SCV000050904 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Blueprint Genetics RCV000208226 SCV000263852 uncertain significance Cardiac arrest 2015-11-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621568 SCV000737809 likely benign Cardiovascular phenotype 2016-11-29 criteria provided, single submitter clinical testing Other strong data supporting benign classification
Illumina Clinical Services Laboratory,Illumina RCV001124514 SCV001283483 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Health, Inc RCV001181081 SCV001346157 likely benign Cardiomyopathy 2019-02-28 criteria provided, single submitter clinical testing
Invitae RCV001124514 SCV001416619 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-09-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 355 of the DSG2 protein (p.Ala355Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DSG2-related disease. ClinVar contains an entry for this variant (Variation ID: 191629). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000171900 SCV001771150 uncertain significance not provided 2021-04-06 criteria provided, single submitter clinical testing Reported in a cohort not selected for arrhythmia, cardiomyopathy or family history of sudden death who underwent exome anaylsis (Ng et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar with conflicting classifications, including variant of uncertain significance and likely benign variant (ClinVar Variant ID# 191629; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 23861362)

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