ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.3167C>T (p.Thr1056Ile) (rs767538450)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766868 SCV000233515 uncertain significance not provided 2018-11-02 criteria provided, single submitter clinical testing p.Thr1056Ile (ACT>ATT): c.3167 C>T in exon 15 of the DSG2 gene (NM_001943.3). At least 12% of patients with autosomal dominant arrhythmogenic right ventricular cardiomyopathy have been reported to have a mutation in the DSG2 gene (McNally E et al., 2009).The T1056I variant in the DSG2 gene has been published as a possible disease-causing mutation (Quarta G et al., 2011; Van der Zwaag P et al., 2009). Although T1056I results in a non-conservative amino acid substitution, the substitution occurs at a position that is not conserved across species. Furthermore, in silico analysis predicts T1056I likely does not alter the protein structure/function. However, two probable mutations nearby (T1047R, S1059T) have been published in association with ARVC, supporting the functional importance of this region of the protein. In addition, the T1056I was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARVC, CARDIOMYOPATHY panel(s).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000181236 SCV000539032 uncertain significance not specified 2016-06-16 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only 1 report; ClinVar: 1 VUS
Invitae RCV000697639 SCV000826262 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-06-07 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1056 of the DSG2 protein (p.Thr1056Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606390). ClinVar contains an entry for this variant (Variation ID: 199821). 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 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769522 SCV000900917 uncertain significance Cardiomyopathy 2017-09-19 criteria provided, single submitter clinical testing
Color Health, Inc RCV000769522 SCV000914137 uncertain significance Cardiomyopathy 2020-11-17 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 1056 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: 21606390). This variant has been identified in 5/249434 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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