ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.877A>T (p.Ile293Leu) (rs2230234)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212490 SCV000233461 likely benign not specified 2014-09-04 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212490 SCV000697890 uncertain significance not specified 2016-07-11 criteria provided, single submitter clinical testing Variant summary: The DSG2 c.877A>T (p.Ile293Leu) variant causes a missense change involving a conserved nucleotide with 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/120730 (1/60365), which exceeds the estimated maximal expected allele frequency for a pathogenic DSG2 variant of 1/100000, however, this observation needs to be cautiously considered due to the cohort potentially harboring phenotypes that could be caused by a DSG2 mutation. The variant of interest, to our knowledge, has not been reported in affected individuals via publications, although a clinical laboratory cites the variant as "likely benign," without additional information for an independent evaluation. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Ambry Genetics RCV000621307 SCV000736753 uncertain significance Cardiovascular phenotype 2019-03-10 criteria provided, single submitter clinical testing The p.I293L variant (also known as c.877A>T), located in coding exon 8 of the DSG2 gene, results from an A to T substitution at nucleotide position 877. The isoleucine at codon 293 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, leucine is the reference amino acid in other 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 variant remains unclear.
Color Health, Inc RCV001184306 SCV001350254 uncertain significance Cardiomyopathy 2020-07-15 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with leucine at codon 293 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 been identified in 3/280772 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 RCV001225861 SCV001398155 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-03-19 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 293 of the DSG2 protein (p.Ile293Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is present in population databases (rs2230234, ExAC 0.003%). This variant has not been reported in the literature in individuals with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 36014). 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: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). 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.

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