Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000150566 | SCV000197818 | pathogenic | Primary dilated cardiomyopathy; Arrhythmogenic right ventricular cardiomyopathy | 2018-01-31 | criteria provided, single submitter | clinical testing | The p.Glu1159fs variant in DSP has been identified in 2 individuals with ARVC an d 1 individual with DCM. It segregated with disease in 5 affected family members from 2 families (Asimaki 2016, LMM data). It was absent from large population s tudies. This variant is predicted to cause a frameshift, which alters the protei n?s amino acid sequence beginning at position 1159 and leads to a premature term ination codon 2 amino acids downstream. This alteration is then predicted to lea d to a truncated or absent protein. Heterozygous loss of function of the DSP gen e is associated with ARVC and DCM. In summary, this variant meets criteria to be classified as pathogenic for ARVC and DCM in an autosomal dominant manner based upon its loss of function impact, case observations, segregation studies, and a bsence from controls. ACMG/AMP Criteria applied: PVS1; PM2; PP1_Moderate; PS4_Su pporting. |
| Invitae | RCV001868081 | SCV002238416 | pathogenic | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 | 2022-06-21 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 517147). This premature translational stop signal has been observed in individual(s) with clinical features of DSP-related conditions (PMID: 31386562, 32372669). This sequence change creates a premature translational stop signal (p.Glu1159Argfs*3) in the DSP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). |
| Ambry Genetics | RCV002457961 | SCV002613947 | pathogenic | Cardiovascular phenotype | 2018-07-22 | criteria provided, single submitter | clinical testing | The c.3474dupA pathogenic mutation, located in coding exon 23 of the DSP gene, results from a duplication of A at nucleotide position 3474, causing a translational frameshift with a predicted alternate stop codon (p.E1159Rfs*3). This alteration has been detected in an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort (Asimaki A et al. Circ Arrhythm Electrophysiol, 2016 Feb;9:e003688). Alterations in DSP that result in haploinsufficiency or protein truncation have been reported in patients with 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 is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |