ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1525G>A (p.Asp509Asn) (rs753406968)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000216245 SCV000271713 uncertain significance not specified 2015-03-21 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Asp509Asn var iant in DSG2 has not been previously reported in individuals with cardiomyopathy , but has been identified in 4/8616 of East Asian chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org). Aspartic acid (Asp) at position 509 is not conserved in mammals or evolutionarily distant species and 3 species (squirrel, ferret, and American alligator) carry an asparagine (Asn) a t this position, raising the possibility that this change may be tolerated. Addi tional computational prediction tools suggest that the p.Asp509Asn variant may n ot impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Asp509As n variant is uncertain, the presence of the variant amino acid in multiple other species suggests that it is more likely to be benign.
Phosphorus, Inc. RCV000577980 SCV000679861 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000578060 SCV000679862 uncertain significance Dilated cardiomyopathy 1BB 2017-08-01 criteria provided, single submitter clinical testing
Invitae RCV000577980 SCV000826659 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 509 of the DSG2 protein (p.Asp509Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs753406968, ExAC 0.05%). This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 29178656). ClinVar contains an entry for this variant (Variation ID: 228629). 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 asparagine 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 and their clinical significance is uncertain. 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 RCV001191827 SCV001359739 uncertain significance Cardiomyopathy 2018-11-26 criteria provided, single submitter clinical testing

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