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

gnomAD frequency: 0.00001  dbSNP: rs753406968

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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 dysplasia 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 dysplasia 10	2023-07-03	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 228629). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 29178656). This variant is present in population databases (rs753406968, gnomAD 0.05%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 509 of the DSG2 protein (p.Asp509Asn).
Color Diagnostics, LLC DBA Color Health	RCV001191827	SCV001359739	uncertain significance	Cardiomyopathy	2022-12-14	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 509 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 been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 29178656). This variant has aslo been identified in 11/249432 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.
Ambry Genetics	RCV002390578	SCV002708208	likely benign	Cardiovascular phenotype	2022-02-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.