ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.8117A>T (p.Lys2706Met) (rs537588390)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000587494 SCV000698449 uncertain significance not provided 2017-01-23 criteria provided, single submitter clinical testing Variant summary: The DSP c.8117A>T (p.Lys2706Met) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 5/121266 control chromosomes at a frequency of 0.0000412, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.000025), suggesting this variant is possibly a benign polymorphism. However, due to limit number of occurrences in ExAC controls, benign classifcation of this variant can not be unequivocally established. 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. Taken together, this variant is classified as VUS.
Color RCV000772488 SCV000905667 uncertain significance Cardiomyopathy 2018-10-29 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the C-terminal plakin repeat domain C of the DSP protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 10/277192 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Invitae RCV000804647 SCV000944564 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-11-06 criteria provided, single submitter clinical testing This sequence change replaces lysine with methionine at codon 2706 of the DSP protein (p.Lys2706Met). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and methionine. This variant is present in population databases (rs537588390, ExAC 0.02%). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 496250). 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 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.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678706 SCV000804870 uncertain significance Dilated cardiomyopathy 2017-08-29 no assertion criteria provided clinical testing

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