Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000466615 | SCV000543222 | pathogenic | Arrhythmogenic right ventricular dysplasia 8 | 2017-05-23 | criteria provided, single submitter | clinical testing | This sequence change inserts 1 nucleotide in exon 24 of the DSP mRNA (c.5745dupT), causing a frameshift at codon 1916. This creates a premature translational stop signal in the last exon of the DSP mRNA (p.Lys1916*). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated DSP protein. While this truncation has not been reported in the literature, a truncating variant located downstream in exon 24 has been reported to be deleterious (PMID: 11063735). For these reasons, this variant has been classified as Pathogenic. |
| Invitae | RCV001383704 | SCV001582954 | pathogenic | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 | 2023-01-10 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals affected with DSP-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Lys1916*) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 956 amino acid(s) of the DSP protein. ClinVar contains an entry for this variant (Variation ID: 405223). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DSP protein in which other variant(s) (p.Thr2634Lysfs*4) have been determined to be pathogenic (PMID: 11063735). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. |
| Ambry Genetics | RCV002348273 | SCV002651633 | pathogenic | Cardiovascular phenotype | 2019-10-28 | criteria provided, single submitter | clinical testing | The c.5745dupT pathogenic mutation, located in coding exon 24 of the DSP gene, results from a duplication of T at nucleotide position 5745. This changes the amino acid at position 1916 from a lysine to a stop codon (p.K1916*). 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 and is not expected to trigger nonsense-mediated mRNA decay; however, it results in the removal of 956 amino acids comprising approximately 33% of the protein. While the exact functional impact of these removed amino acids is unknown, the eliminated regions include the plakin repeats, plectin domains, tandem repeats of G-S-R-[SR], and domains required for keratin and intermediate filament interaction. In addition, several alterations more C-terminal than this variant have been detected in ARVC and DCM cohorts (e.g., c.8077_8080delAAG and c.8188delC in Walsh R et al. Genet. Med. 2017;19:192-203). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |