Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000578822 | SCV000680619 | pathogenic | not provided | 2021-01-27 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek et al., 2016); Nonsense 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: 31402444, 27532257, 31514951, 30919684, 20738328, 19924139, 28416588, 17531221, 16175511, 20400443, 28527814) |
| Labcorp Genetics |
RCV001048758 | SCV001212777 | pathogenic | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 | 2023-12-19 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg1934*) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 938 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 DSP-related conditions (PMID: 16175511, 28416588, 30919684). ClinVar contains an entry for this variant (Variation ID: 16843). This variant disrupts a region of the DSP protein in which other variant(s) (p.Gln2730Serfs*16) have been determined to be pathogenic (PMID: 27532257, 28527814). 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. |
| Clinical Genetics Laboratory, |
RCV000578822 | SCV005197785 | pathogenic | not provided | 2022-10-26 | criteria provided, single submitter | clinical testing | |
| Molecular Genetics, |
RCV005249991 | SCV005900389 | pathogenic | Primary dilated cardiomyopathy | 2024-05-02 | criteria provided, single submitter | clinical testing | This sequence change in DSP is a nonsense variant predicted to cause a premature stop codon, p.(Arg1934*), in the last biologically relevant exon. This leads to loss of 938 amino acids from the C-terminal end of the protein (~32% of the protein) and is predicted to escape nonsense-mediated decay. However truncation of this region includes all three intermediate filament-binding sub-domains (amino acids 1946-2871), which are critical for DSP function and loss-of-function is an established disease mechanism (PMID: 16175511, 17934502, 27532257, 31514951). This variant is absent from the population database gnomAD v4.0. ClinVar contains an entry for this variant (ID: 16843). This variant has been observed in at least 4 heterozygous individuals with features of DSP-related disorders (PMID: 37450050, 20400443, 28416588, 30919684). This variant has been observed in the compound heterozygous state, confirmed in trans, with another pathogenic DSP truncating C-terminal variant (c.6370delTT) in an infant with lethal acantholytic epidermolysis bullosa (PMID: 16175511). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3, PM2_Supporting, PS4_Supporting. |
| OMIM | RCV000018337 | SCV000038616 | pathogenic | Lethal acantholytic epidermolysis bullosa | 2005-10-01 | no assertion criteria provided | literature only |