ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2690C>A (p.Ala897Asp) (rs765238150)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181232 SCV000233511 uncertain significance not provided 2013-01-16 criteria provided, single submitter clinical testing p.Ala897Asp (GCC>GAC): c.2690 C>A in exon 15 of the DSG2 gene (NM_001943.3). The Ala897Asp variant in the DSG2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ala897Asp results in a non-conservative amino acid substitution of a non-polar Alanine with a negatively charged Aspartic acid at a position that is not uniformly conserved across species. The Ala897Asp 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. Nevertheless, in silico analysis predicts Ala897Asp is benign to the protein structure/function. Additionally, no mutations in nearby codons have been reported in association with ARVC. With the information available at this time, we cannot definitively determine if Ala897Asp is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s).
Invitae RCV000796747 SCV000936273 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2018-07-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 897 of the DSG2 protein (p.Ala897Asp). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is present in population databases (rs765238150, ExAC 0.008%). This variant has not been reported in the literature in individuals with DSG2-related disease. ClinVar contains an entry for this variant (Variation ID: 199818). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; 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.
Color Health, Inc RCV001526107 SCV001736392 uncertain significance Cardiomyopathy 2020-10-19 criteria provided, single submitter clinical testing This missense variant replaces alanine with aspartic acid at codon 897 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 9/280358 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.

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