Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000533748 | SCV000641311 | uncertain significance | Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 | 2017-11-10 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine with arginine at codon 1489 of the DSP protein (p.Leu1489Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is present in population databases (rs746782582, ExAC 0.01%) 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: "Benign"; 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. |
| CHEO Genetics Diagnostic Laboratory, |
RCV000770245 | SCV000901676 | uncertain significance | Cardiomyopathy | 2017-10-30 | criteria provided, single submitter | clinical testing | |
| Integrated Genetics/Laboratory Corporation of America | RCV000780217 | SCV000917306 | uncertain significance | not specified | 2019-03-25 | criteria provided, single submitter | clinical testing | Variant summary: DSP c.4466T>G (p.Leu1489Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.5e-05 in 275570 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4466T>G in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |