ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.692A>G (p.Tyr231Cys) (rs770210088)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000423839 SCV000526983 uncertain significance not provided 2019-01-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. The Y231C variant has not been published as pathogenic or been reported as benign to our knowledge. The Y231C 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). Additionally, Y231C 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. Furthermore, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant has not been observed in a significant number of affected individuals and it lacks both segregation and functional studies which would further clarify its pathogenicity.
Invitae RCV000526876 SCV000641339 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 231 of the DSP protein (p.Tyr231Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs770210088, ExAC 0.01%) but has not been reported in the literature in individuals with a DSP-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000771993 SCV000904948 uncertain significance Cardiomyopathy 2018-04-20 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the plakin domain of the DSP protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant 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. This variant has been identified in 3/277172 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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