ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.6566G>A (p.Arg2189Gln) (rs766933370)

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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 RCV000588624 SCV000698444 uncertain significance not provided 2017-06-26 criteria provided, single submitter clinical testing Variant summary: The DSP c.6566G>A (p.Arg2189Gln) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 4/121402 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.000288 (3/10406). This frequency is about 12 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. However, the possibility of sublinical cardiac disease in the ExAC cohort of 4 individuals cannot be excluded . The variant has been reported in the literature in one arrythmia patient, without strong evidence for causality. The variant has not, to our knowledge, been reported by databases or reputable clinical labs. Taken together, this variant is classified as VUS-possibly benign.
Invitae RCV000707496 SCV000836596 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-06-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 2189 of the DSP protein (p.Arg2189Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs766933370, ExAC 0.03%). This variant has been observed in an individual affected with left ventricular hypertrabeculation (PMID: 28798025) and in an individual affected with arrhythmia (PMID: 26688388). ClinVar contains an entry for this variant (Variation ID: 496248). 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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