ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.2675G>A (p.Arg892His) (rs758592774)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000685917 SCV000813418 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-06-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 892 of the DSP protein (p.Arg892His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs758592774, ExAC 0.009%). 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Integrated Genetics/Laboratory Corporation of America RCV000781335 SCV000919294 uncertain significance not specified 2018-04-16 criteria provided, single submitter clinical testing Variant summary: DSP c.2675G>A (p.Arg892His) results in a non-conservative amino acid change located in the Spectrin/alpha-actinin of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 246050 control chromosomes (gnomAD). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. However, the total number of occurrence is rather small. The variant, c.2675G>A, has been reported in the literature in an individual diagnosed with Brugada Syndrome (Quenin_2017). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.

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