Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001207622 | SCV001378984 | pathogenic | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 | 2020-01-24 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the DSP gene (p.Lys1996Argfs*37). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 876 amino acids of the DSP protein. This variant has not been reported in the literature in individuals with DSP-related conditions. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the DSP protein. Other variant(s) that disrupt this region (p.Arg2160*, p.Lys2693Profs*3, p.Thr2733Serfs*14, p.Gln2765Alafs*23) have been determined to be pathogenic (PMID: 28527814, 21859740). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. |
| Ambry Genetics | RCV002356890 | SCV002658740 | pathogenic | Cardiovascular phenotype | 2019-04-09 | criteria provided, single submitter | clinical testing | The c.5987delA pathogenic mutation, located in coding exon 24 of the DSP gene, results from a deletion of one nucleotide at nucleotide position 5987, causing a translational frameshift with a predicted alternate stop codon (p.K1996Rfs*37). Alterations in DSP that result in haploinsufficiency or protein truncation have been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM) (Fressart V et al. Europace. 2010;12(6):861-8; Elliott P et al. Circ Cardiovasc Genet. 2010;3(4):314-22; Quarta G et al. Circulation. 2011;123(23):2701-9; Garcia-Pavia P et al. Heart. 2011;97(21):1744-52; Rasmussen TB et al. Clin Genet. 2013;84(1):20-30; Pugh TJ et al. Genet Med. 2014;16(8):601-8). This alteration occurs at the 3' terminus of DSP, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 876 amino acids of the protein. While the exact functional impact of these amino acids is unknown at this time, the eliminated amino acids include most of the plakin repeat regions, 16 plectin domains and 6 X 4 AA tandem repeats of G-S-R-[SR], and a number of alterations more C-terminal than this variant have been detected in arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM) cohorts (e.g., c.8077_8080delAAG and c.8188delC in Walsh R et al. Genet. Med. 2017;19:192-203). This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. |