ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.2719C>T (p.Arg907Cys) (rs749051278)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000404899 SCV000464946 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000304284 SCV000464947 uncertain significance Ectodermal dysplasia skin fragility syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000354548 SCV000464948 uncertain significance Skin fragility woolly hair syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000394733 SCV000464949 uncertain significance Epidermolysis bullosa, lethal acantholytic 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000470197 SCV000543277 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2016-10-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 907 of the DSP protein (p.Arg907Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs749051278, ExAC 0.006%) but has not been reported in the literature in individuals with a DSP-related disease. 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. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757185 SCV000885322 uncertain significance not provided 2018-05-24 criteria provided, single submitter clinical testing The p.Arg907Cys variant (rs749051278) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. A variant that affects the same codon (p.Arg907His) was reported in a patient with dilated cardiomyopathy, however, without a clinical significance (Cuenca 2016). The p.Arg907Cys variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.002 percent (identified on 4 out of 246,106 chromosomes) and has been reported to the ClinVar database (Variation ID: 357945). The arginine at position 907 is moderately conserved considering 12 species (Alamut v2.11) and computational analyses of the p.Arg907Cys variant on protein structure and function indicate a deleterious effect (SIFT: damaging, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Arg907Cys variant with certainty.

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