ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.6307A>G (p.Lys2103Glu) (rs149513743)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181387 SCV000233689 uncertain significance not provided 2017-04-12 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. The K2103E variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 14/66,552 (0.021%) alleles from individuals of European ancestry in the ExAC dataset (Lek et al., 2016). The K2103E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis suggests that this variant is probably damaging to the protein structure/function. This substitution occurs at a position that is conserved across most species; however glutamic acid is present as the wild type in at least one species.
Illumina Clinical Services Laboratory,Illumina RCV000318076 SCV000465162 uncertain significance Skin fragility woolly hair syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000375062 SCV000465163 uncertain significance Ectodermal dysplasia skin fragility syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000259235 SCV000465164 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000316774 SCV000465165 uncertain significance Epidermolysis bullosa, lethal acantholytic 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000477049 SCV000543249 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 2103 of the DSP protein (p.Lys2103Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs149513743, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 28416588). 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.
CSER_CC_NCGL; University of Washington Medical Center RCV000259235 SCV000700096 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2016-10-01 criteria provided, single submitter research Found in patient having exome sequencing for an unrelated indication. No known history of arrhythmogenic right ventricular dysplasia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Color RCV000777748 SCV000913710 uncertain significance Cardiomyopathy 2018-10-04 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 A of the DSP protein that binds intermediate filaments. Computational prediction tools and conservation analyses suggest that this variant may not impact 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. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 28416588). This variant has also been identified in 37/277208 chromosomes (32/126708 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Blueprint Genetics RCV000157206 SCV000206930 uncertain significance Primary dilated cardiomyopathy 2014-09-29 no assertion criteria provided clinical testing

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