ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.2037A>G (p.Ile679Met) (rs151049942)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457923 SCV000543261 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2016-08-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 679 of the DSP protein (p.Ile679Met). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs151049942, ExAC 0.05%) but has not been reported in the literature in individuals with a 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. In summary, this variant is a rare missense change that is not predicted to affect 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.
Integrated Genetics/Laboratory Corporation of America RCV000588384 SCV000698421 likely benign not provided 2017-01-03 criteria provided, single submitter clinical testing Variant summary: The DSP c.2037A>G (p.Ile679Met) variant involves the alteration of a non-conserved nucleotide, which 3/3 in silico tools (SNPs&GO and MutationTaster not captured due to low reliability index and p-value, respectively) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 5/121348 (1/24271), predominantly in the African cohort, 5/10394 (1/2079), which exceeds the estimated maximal expected allele frequency for a pathogenic DSP variant of 1/40000. Therefore, suggesting this is likely a benign polymorphism found primarily in population(s) of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Therefore, the variant of interest has been classified as "likely benign," until additional information becomes available (ie, clinical and functional studies).

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