ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.1468C>T (p.Arg490Cys) (rs781084693)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181290 SCV000233580 uncertain significance not provided 2014-04-15 criteria provided, single submitter clinical testing p.Arg490Cys (CGC>TGC): c.1468 C>T in exon 12 of the DSP gene (NM_004415.2). The R490C variant has not been published as a mutation or as a benign polymorphism to our knowledge. The R490C 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 R490C 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, no definitive disease-causing missense mutations in a nearby residues have been reported in association with ARVC, suggesting that this region of the protein may tolerate variation. 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 ARRHYTHMIA panel(s).
Color RCV000778029 SCV000914141 uncertain significance Cardiomyopathy 2018-08-28 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the spectrin repeat 5 of the plakin domain of the DSP protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 8/246194 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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