ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.5062G>A (p.Ala1688Thr) (rs757753880)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520322 SCV000619706 uncertain significance not provided 2017-08-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. The A1688T variant has not been published as pathogenic or been reported as benign to our knowledge. The A1688T variant is observed in 7/66170 (0.01%) alleles from individuals of Non-Finnish European background in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016). The A1688T 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, this substitution occurs at a position that is not conserved and threonine (T) is the wild type amino acid at this position in multiple species. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function.
Invitae RCV000796190 SCV000935693 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1688 of the DSP protein (p.Ala1688Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs757753880, ExAC 0.01%). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 451060). 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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