ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.643G>A (p.Glu215Lys) (rs148095061)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154707 SCV000204386 uncertain significance not specified 2014-02-20 criteria provided, single submitter clinical testing The Glu215Lys variant in DSP has not been previously reported in individuals wit h cardiomyopathy, but has been identified in 1/8600 European American chromosome s by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSN P rs147315869). Computational analyses (biochemical amino acid properties, conse rvation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Glu215Lys variant may impact the normal function of the protein, though this information is not predic tive enough to determine pathogenicity. Additional information is needed to full y assess the clinical significance of the Glu215Lys variant.
Invitae RCV000466856 SCV000543239 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2016-09-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 215 of the DSP protein (p.Glu215Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs148095061, ExAC 0.009%) but has not been reported in the literature in individuals with a DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 178024). 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 RCV000776301 SCV000911602 uncertain significance Cardiomyopathy 2018-06-05 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the spectrin repeat 3 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 19/277134 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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