ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.545A>G (p.Asn182Ser) (rs368512832)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 cardiomyopathy, type 10 2020-06-29 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 182 of the DSG2 protein (p.Asn182Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs368512832, ExAC 0.05%). This variant has been reported in an individual affected with infantile dilated cardiomyopathy (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 44323). 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 serine amino acid residue is also 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000766579 SCV000518616 uncertain significance not provided 2017-10-30 criteria provided, single submitter clinical testing The N182S variant of uncertain significance in the DSG2 gene was reported as a likely benign variant in association with DCM, at least one patient also harbored several other variants in cardiomyopathy-related genes (Pugh et al., 2014; Walsh et al., 2017). Similarly, this variant has been identified in conjunction with additional cardiogenetic variants in several individuals referred for cardiomyopathy genetic testing at GeneDx. The N182S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Moreover, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. Finally, the N182S variant is observed in 13/24018 (0.05%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016).
Ambry Genetics RCV000620980 SCV000737989 uncertain significance Cardiovascular phenotype 2020-08-27 criteria provided, single submitter clinical testing The p.N182S variant (also known as c.545A>G), located in coding exon 6 of the DSG2 gene, results from an A to G substitution at nucleotide position 545. The asparagine at codon 182 is replaced by serine, an amino acid with highly similar properties. This alteration has been detected in an individual from a hypertrophic cardiomyopathy cohort, and an individual with infantile dilated cardiomyopathy, both of whom also had variants in other cardiac-related genes (Lopes LR et al. J Med Genet. 2013;50:228-39; Pugh TJ et al. Genet Med. 2014;16:601-8). This amino acid position is poorly conserved in available vertebrate species, and serine 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.
Color Health, Inc 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.

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