Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000556858 | SCV000641330 | pathogenic | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 | 2023-12-21 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Leu2031Glyfs*29) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 841 amino acid(s) of the DSP protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal recessive Carvajal syndrome (PMID: 31073624). This variant has been reported in individual(s) with autosomal recessive lethal acantholytic epidermolysis bullosa (PMID: 16175511); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 16844). This variant disrupts a region of the DSP protein in which other variant(s) (p.Gln2667*) have been determined to be pathogenic (PMID: 20400443, 27194543). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002354164 | SCV002656286 | pathogenic | Cardiovascular phenotype | 2018-06-05 | criteria provided, single submitter | clinical testing | The c.6091_6092delTT pathogenic mutation, located in coding exon 24 of the DSP gene, results from a deletion of two nucleotides at nucleotide positions 6091 to 6092, causing a translational frameshift with a predicted alternate stop codon (p.L2031Gfs*29). 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 841 amino acids of the protein. While the exact functional impact of these removed amino acids is unknown at this time, the eliminated amino acids include 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). Furthermore, this alteration has been reported in the compound heterozygous state in a neonate with lethal acantholytic epidermolysis bullosa (Jonkman MF et al. Am. J. Hum. Genet. 2005;77:653-60). In addition to the clinical data presented in the literature, 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. |
| Fulgent Genetics, |
RCV002490384 | SCV002802292 | pathogenic | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8; Lethal acantholytic epidermolysis bullosa; Woolly hair-skin fragility syndrome; Keratosis palmoplantaris striata 2; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis | 2021-10-16 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV003329232 | SCV004036910 | pathogenic | not provided | 2023-09-22 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31073624, 34998950, 16175511) |
| OMIM | RCV000018338 | SCV000038617 | pathogenic | Lethal acantholytic epidermolysis bullosa | 2005-10-01 | no assertion criteria provided | literature only |