ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.581C>T (p.Ser194Leu) (rs374875442)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037312 SCV000060969 uncertain significance not specified 2016-05-27 criteria provided, single submitter clinical testing The p.Ser194Leu variant in DSG2 has been reported in a compound heterozygous ind ividual with ARVC (Nakajima 2012). In addition, this variant has been identified by our laboratory in one child with clinical features of DCM and ARVD/C. It has been identified in 3/16492 South Asian chromosomes by the Exome Aggregation Con sortium (ExAC, http://exac.broadinstitute.org; dbSNP rs374875442). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine path ogenicity. In summary, the clinical significance of the p.Ser194Leu variant is u ncertain.
Invitae RCV000642313 SCV000763982 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2017-12-04 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 194 of the DSG2 protein (p.Ser194Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs374875442, ExAC 0.02%). This variant has been observed on the opposite chromosome (in trans) from a rare missense variant in an individual affected with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) (PMID 22214898). ClinVar contains an entry for this variant (Variation ID: 44324). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV001560109 SCV001782450 uncertain significance not provided 2019-10-25 criteria provided, single submitter clinical testing Reported with a different missense variant on the opposite allele (in trans) in an individual with ARVC, and observed in apparent homozygous state in another individual with ARVC in published literature (Nakajima et al., 2012; Shapieva et al., 2014); in one family, S194L segregated in an unaffected relative and a relative whose echocardiogram showed a minor right ventricular structural abnormality, but their EKG was not suggestive of ARVC (Nakajima et al., 2012); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 44324; Landrum et al., 2016), and one clinical laboratory identified this variant in a child with clinical features of DCM and ARVC (SCV000060969.4; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30177324, 22214898, 23299917)

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