ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.3146C>T (p.Ser1049Leu) (rs751361395)

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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 RCV000366711 SCV000464974 uncertain significance Ectodermal dysplasia skin fragility syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000272182 SCV000464975 uncertain significance Epidermolysis bullosa, lethal acantholytic 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000322535 SCV000464976 uncertain significance Skin fragility woolly hair syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000379457 SCV000464977 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000470079 SCV000543260 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2016-05-15 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 1049 of the DSP protein (p.Ser1049Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs751361395, ExAC 0.05%) 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000485378 SCV000571666 uncertain significance not provided 2017-05-23 criteria provided, single submitter clinical testing The S1049L variant has not been published as pathogenic or been reported as benign to our knowledge. TheS1049L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structureas these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at aposition that is conserved through mammals. Nonetheless, in silico analysis is inconsistent in its predictions as towhether or not the variant is damaging to the protein structure/function. Finally, this variant is observed in 7/119952alleles globally in the ExAC dataset with the highest allele frequency occurring in individuals of Finnish ancestry(3/6608 alleles; 0.05%) (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

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