ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.175C>T (p.Arg59Trp)

gnomAD frequency: 0.00005  dbSNP: rs749602291
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521028 SCV000620087 uncertain significance not provided 2017-08-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSG2 gene. The R59W variant has not been published as pathogenic or been reported as benign to our knowledge. The R59W variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R59W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved and tryptophan (W) is the wild-type amino acid at this position in at least two species. Consequently, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Color Diagnostics, LLC DBA Color Health RCV001805137 SCV002052096 uncertain significance Cardiomyopathy 2023-05-10 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 59 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 13/280864 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.
Invitae RCV001858002 SCV002173318 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2023-04-08 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 451391). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. This variant is present in population databases (rs749602291, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 59 of the DSG2 protein (p.Arg59Trp).

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