ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.4754C>T (p.Ser1585Leu) (rs773622004)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000589614 SCV000698436 uncertain significance not provided 2017-02-20 criteria provided, single submitter clinical testing Variant summary: The DSP c.4754C>T (p.Ser1585Leu) variant involves the alteration of a non-conserved nucleotide and is predicted to be benign by 4/5 in silico tools. This variant is located outside of some of known domains/repeats (InterPro, UniProt). This variant was found in 1/119252 control chromosomes from ExAC at a frequency of 0.0000084, which does not exceed the estimated maximal expected allele frequency of a pathogenic DSP variant (0.00001). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000641775 SCV000763423 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-03-15 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 1585 of the DSP protein (p.Ser1585Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs773622004, ExAC 0.002%). This variant has not been reported in the literature in individuals with DSP-related disease. 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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