ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.8500C>T (p.Arg2834Cys) (rs753033333)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000202757 SCV000257972 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2015-07-17 criteria provided, single submitter clinical testing
GeneDx RCV000480458 SCV000565934 uncertain significance not provided 2015-12-03 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. Although the R2834C variant has not been published as a pathogenic variant or as a benign variant to our knowledge, it has previously been identified in one other unrelated individual who had genetic testing for cardiomyopathy at GeneDx and was classified as a variant of uncertain significance by another clinical laboratory (Landrum et al., 2014). In addition, a different missense variant affecting the same amino acid residue (R2834H) has been reported in association with ARVC (Yang et al., 2006); this variant was absent from 400 control chromosomes. Functional studies suggest R2834H may contribute to disease by disrupting desmosomal integrity (Yang et al., 2006; Albrecht et al., 2015).The R2834C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R2834C 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. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no other missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000821527 SCV000962286 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2019-01-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2834 of the DSP protein (p.Arg2834Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs753033333, ExAC 0.01%). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 218636). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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.

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