Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000617883 | SCV000737770 | uncertain significance | Cardiovascular phenotype | 2023-04-18 | criteria provided, single submitter | clinical testing | The p.L1451P variant (also known as c.4352T>C), located in coding exon 23 of the DSP gene, results from a T to C substitution at nucleotide position 4352. The leucine at codon 1451 is replaced by proline, an amino acid with similar properties. This alteration has been reported in a sudden unexplained death cohort and a cardiomyopathy genetic testing cohort; however, clinical details were limited in both cases (Bagnall RD et al. N Engl J Med, 2016 Jun;374:2441-52; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Agnes Ginges Centre for Molecular Cardiology, |
RCV000853465 | SCV000996376 | uncertain significance | Sudden unexplained death | 2017-05-03 | criteria provided, single submitter | research | The DSP Leu1451Pro was identified in a sudden death case, with no previous diagnosis and no definitive cause found on post mortem (Bagnall RD, et al., 2016). The variant is absent from the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Computational tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be deleterious. Based on the limited information available and rarity in the general population, we classify DSP Leu1451Pro as a variant of "uncertain significance". |
| Human Genome Sequencing Center Clinical Lab, |
RCV001258158 | SCV001435046 | uncertain significance | Arrhythmogenic right ventricular dysplasia 8 | criteria provided, single submitter | clinical testing | ||
| Invitae | RCV001860388 | SCV002288363 | uncertain significance | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 | 2021-02-02 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) affected by sudden cardiac death (PMID: 27332903). ClinVar contains an entry for this variant (Variation ID: 519346). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 1451 of the DSP protein (p.Leu1451Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. |