ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2269A>T (p.Met757Leu)

gnomAD frequency: 0.00002  dbSNP: rs750010743
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001178763 SCV001343275 uncertain significance Cardiomyopathy 2019-12-20 criteria provided, single submitter clinical testing This missense variant replaces methionine with leucine at codon 757 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/245294 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 RCV001206928 SCV001378262 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2022-07-26 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 757 of the DSG2 protein (p.Met757Leu). This variant is present in population databases (rs750010743, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 920182). 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 leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics RCV002445421 SCV002738001 uncertain significance Cardiovascular phenotype 2021-02-24 criteria provided, single submitter clinical testing The p.M757L variant (also known as c.2269A>T), located in coding exon 14 of the DSG2 gene, results from an A to T substitution at nucleotide position 2269. The methionine at codon 757 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species, and 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 alteration remains unclear.

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