ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.5173C>T (p.Arg1725Trp) (rs200336897)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000440169 SCV000535801 uncertain significance not provided 2017-01-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. The R1725W variant has not been publishedas a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject. The R1725W variant is a non-conservative amino acidsubstitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, sizeand/or other properties. Moreover, this substitution occurs at a position that is conserved across species, and in silicoanalysis predicts this variant is probably damaging to the protein structure/function. Nonetheless, this variant lacksobservation in a significant number of affected individuals, segregation data, and functional evidence, all of whichwould further clarify pathogenicity.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.This result cannot be interpreted for diagnosis or used for family member screening at this time.
Invitae RCV000472043 SCV000543237 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2017-04-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1725 of the DSP protein (p.Arg1725Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs200336897, ExAC 0.03%). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 26084686). 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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