ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.6062C>G (p.Ala2021Gly) (rs760673242)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621984 SCV000735860 uncertain significance Cardiovascular phenotype 2017-04-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000766953 SCV000571991 uncertain significance not provided 2017-07-24 criteria provided, single submitter clinical testing The A2021G variant of uncertain significance in the DSP gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A2021G variant of uncertain significance in the DSP gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at any significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A2021G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Moreover, this substitution occurs at a position that is not conserved across species. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000641794 SCV000763443 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2017-08-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 2021 of the DSP protein (p.Ala2021Gly). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs760673242, ExAC 0.002%). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 228644). 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: "Possibly 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000215746 SCV000271736 uncertain significance not specified 2015-04-16 criteria provided, single submitter clinical testing The p.Ala2021Gly variant in DSP has not been previously reported in individuals with cardiomyopathy, but been identified in 1/66550 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Computation al prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ala2021Gly varian t is uncertain.

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