ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1478A>G (p.Asn493Ser) (rs375679311)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171832 SCV000054851 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2018-04-05 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000150540 SCV000197758 uncertain significance not specified 2014-06-26 criteria provided, single submitter clinical testing The Asn493Ser variant in DSG2 has been reported in 1 individual with ARVC (Quart a 2011). It has also been identified in 1/8302 of European American chromosomes and 1/3874 of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS, Andreasen 2013), as well as in 1/1740 Europe an chromosomes by the ClinSeq Project (dbSNP rs375679311, Ng 2013). Computationa l prediction tools and conservation analysis do not provide strong support for o r against an impact to the protein. In summary, the clinical significance of the Asn493Ser variant is uncertain.
GeneDx RCV000766863 SCV000233497 uncertain significance not provided 2014-10-10 criteria provided, single submitter clinical testing p.Asn493Ser (AAC>AGC):c.1478 A>G in exon 11 of the DSG2 gene (NM_001943.3). The Asn493Ser variant in the DSG2 gene has been reported as a possible disease-causing mutation in association ARVC (Quarta G et al., 2011) and as an unclassified variant (Van der Zwaag P et al., 2009). Although Asn493Ser results in a conservative amino acid substitution of one neutral, polar amino acid for another, this substitution occurs at a position in the cadherin 4 domain which is conserved across species. However, there are no definitive mutations near Asn493Ser, indicating this region of DSG2 gene may be tolerant of change. With the information available, we cannot definitively determine if Asn493Ser is a disease-causing mutation or a rare benign variant. The variant is found in ARVC, ARRHYTHMIA panel(s).
Ambry Genetics RCV000246903 SCV000320424 uncertain significance Cardiovascular phenotype 2020-06-24 criteria provided, single submitter clinical testing The p.N493S variant (also known as c.1478A>G), located in coding exon 11 of the DSG2 gene, results from an A to G substitution at nucleotide position 1478. The asparagine at codon 493 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in one individual with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Quarta G, Circulation 2011 Jun; 123(23):2701-9). This alteration was also identified in an exome cohort in a Caucasian female with sinus bradycardia and left atrial abnormality (Ng D et al. Circ Cardiovasc Genet. 2013;6(4):337-46). This variant has also been seen in other exome cohorts not selected for cardiovascular phenotypes; however, cardiovascular history was not provided (Andreasen C et al. Eur J Hum Genet. 2013;21(9):918-28; Thauvin-Robinet C et al. Eur. J. Hum. Genet. 2019 08;27(8):1197-1214). This amino acid position is highly conserved in available 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 variant remains unclear.
Invitae RCV000458560 SCV000551013 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-10-13 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 493 of the DSG2 protein (p.Asn493Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs375679311, ExAC 0.01%). This variant has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606390). ClinVar contains an entry for this variant (Variation ID: 163212). 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 disruptive, but 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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000458560 SCV000883081 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2018-11-21 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770552 SCV000902000 uncertain significance Cardiomyopathy 2016-02-04 criteria provided, single submitter clinical testing
Mendelics RCV000766863 SCV001135118 uncertain significance not provided 2019-05-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000770552 SCV001356727 uncertain significance Cardiomyopathy 2021-02-19 criteria provided, single submitter clinical testing This missense variant replaces asparagine with serine at codon 493 of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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: 21606390). This variant has also been identified in 17/280812 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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