ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.818A>C (p.Glu273Ala)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002427830 SCV002679651 uncertain significance Cardiovascular phenotype 2019-09-04 criteria provided, single submitter clinical testing The p.E273A variant (also known as c.818A>C), located in coding exon 7 of the DSG2 gene, results from an A to C substitution at nucleotide position 818. The glutamic acid at codon 273 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species; however, alanine 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV003631251 SCV004513621 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2023-11-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 273 of the DSG2 protein (p.Glu273Ala). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 1762334). 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 with a negative predictive value of 95%. 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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