Submissions for variant NM_001943.5(DSG2):c.545A>G (p.Asn182Ser)

gnomAD frequency: 0.00013  dbSNP: rs368512832

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037311	SCV000060968	likely benign	not specified	2015-04-13	criteria provided, single submitter	clinical testing	p.Asn182Ser in exon 6 of DSG2: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, multiple mammals, including cat, dog, rock hyrax, and armadillo, have a seri ne (Ser) at this position despite high nearby amino acid conservation. In additi on, computational prediction tools do not suggest a high likelihood of impact to the protein. This variant has also been identified in 5/9798 African chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs368512832).
Invitae	RCV000226293	SCV000287245	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 182 of the DSG2 protein (p.Asn182Ser). This variant is present in population databases (rs368512832, gnomAD 0.05%). This missense change has been observed in individual(s) with dilated or hypertrophic cardiomyopathy (PMID: 23396983, 24503780, 25351510, 31983221). ClinVar contains an entry for this variant (Variation ID: 44323). 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.
GeneDx	RCV000766579	SCV000518616	uncertain significance	not provided	2022-04-07	criteria provided, single submitter	clinical testing	Reported in association with HCM and DCM, including an African American female with infantile-onset DCM who harbored additional disease-related variants (Lopes et al., 2013; Pugh et al., 2014; Walsh et al., 2017; Mazzarotto et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 31983221, 24503780, 23396983, 25351510)
Ambry Genetics	RCV000620980	SCV000737989	likely benign	Cardiovascular phenotype	2023-04-20	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.
Color Diagnostics, LLC DBA Color Health	RCV001189713	SCV001357063	likely benign	Cardiomyopathy	2019-07-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037311	SCV001361557	likely benign	not specified	2019-11-25	criteria provided, single submitter	clinical testing	Variant summary: DSG2 c.545A>G (p.Asn182Ser) results in a conservative amino acid change located in the second cadherin repeat (IPR002126) of the encoded protein sequence, which might affect a potential N-glycosylation site (Debus_2019). Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 280730 control chromosomes, predominantly at a frequency of 0.00058 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. The variant, c.545A>G, has been reported in the literature in individuals affected with hypertrophic- or dilated cardiomyopathy, however without strong evidence for causality (Lopes_2013, Pugh_2014, Walsh_2017). In addition, co-occurrence with another pathogenic variant has been reported (TTR c.424G>A, p.Val142Ile; in an internal LCA sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have cited the variant as uncertain significance (4x) or likely benign (1x). Based on the evidence outlined above, the variant was classified as likely benign.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000766579	SCV000924769	uncertain significance	not provided	2016-05-13	no assertion criteria provided	provider interpretation	p.Asn182Ser (c.545A>G) in the DSG2 gene (NM_01943.3) We have seen this in one African-American adult with mild dilated cardiomyopathy and a family history suspicious for familial dilated cardiomyopathy. Given the frequency in the general population, the weak case data, the lack of conservation, and the poor match with the family’s phenotype, we consider this a variant of uncertain significance, probably benign. The variant has been seen in at least 1 unrelated case of dilated cardiomyopathy (DCM) (not including this patient's family). Pugh et al (2014) identified the variant in a female infant with a clinical diagnosis of DCM who was of “Black or African American” ethnicity. Variants in several other genes (TTN, DSP, MYH6, MYL3) were also identified in this patient. No family history or segregation data is available. Per the lab report: “The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In addition, the serine amino acid residue is found in multiple mammalian species, suggesting that this missense changes does not adversely affect protein function.” The variant was seen in 6 of ~60,000 individuals listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 3/10/16). The variant is seen in 5 out of 9798 (AF=0.0005103) African alleles and 1 out of 8612 (AF=0.0001161) East Asian alleles. No other variant at the same codon is listed in this database.