ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.3277G>A (p.Ala1093Thr) (rs1185986064)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498000 SCV000589724 uncertain significance not provided 2018-10-18 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. The A1093T variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). The A1093T 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. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000815614 SCV000956075 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1093 of the DSP protein (p.Ala1093Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 432051). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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