ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.145C>T (p.Arg49Cys) (rs762526848)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519693 SCV000618572 likely pathogenic not provided 2018-11-20 criteria provided, single submitter clinical testing The R49C variant has been reported in one individual from a cohort of individuals with HCM, DCM, and ARVC from the United Kingdom, though no patient-specific details were provided (Walsh et al., 2017). The R49C 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. Moreover, this substitution disrupts an arginine (R) residue in R-X-K-R furin-cleavage motif, which is absolutely conserved across species (Awad et al., 2006). In silico analysis predicts this variant is probably damaging to the protein structure/function. Another missense variant at the same residue (R49H) has been reported in the Human Gene Mutation Database in association with ARVC (Stenson et al., 2014), further supporting the functional importance of this region of the protein. Finally, the R49C variant has not been observed in large population cohorts (Lek et al., 2016).
Color Health, Inc RCV001524188 SCV001733966 uncertain significance Cardiomyopathy 2021-02-12 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 49 of the DSG2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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: 27532257). This variant has been identified in 2/249476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg49His, is known to cause arrhythmogenic right ventricular cardiomyopathy (Clinvar variation ID 16810), indicating that arginine at this position is important for DSG2 protein function. 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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