ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.5617C>T (p.Arg1873Cys) (rs144392839)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208104 SCV000263877 uncertain significance Primary dilated cardiomyopathy 2015-05-20 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000333252 SCV000465142 uncertain significance Epidermolysis bullosa, lethal acantholytic 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000387699 SCV000465143 uncertain significance Skin fragility woolly hair syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000274935 SCV000465144 uncertain significance Ectodermal dysplasia skin fragility syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000330069 SCV000465145 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000480327 SCV000568862 uncertain significance not specified 2015-11-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. The R1873C variant has not been published as a pathogenic variant, however, it has been reported in 1/427 ostensibly healthy controls (Kapplinger et al., 2011). Nevertheless, this variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1873C 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. This substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, missense variants in nearby residues have not been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating that this region of the gene is not known to harbor disease-causing variants. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000539472 SCV000641323 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1873 of the DSP protein (p.Arg1873Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs144392839, ExAC 0.06%) but has not been reported in the literature in individuals with a DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 222581). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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