Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000156517 | SCV000206236 | likely pathogenic | Arrhythmogenic right ventricular cardiomyopathy | 2021-01-06 | criteria provided, single submitter | clinical testing | The p.Glu584GlyfsX52 variant in DSP has been identified by our laboratory in 1 individual with dilated cardiomyopathy (DCM) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 584 and lead to a premature termination codon 52 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the DSP gene is an established disease mechanism in autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) and autosomal recessive Carvajal syndrome. DSP loss of function variants have also been reported in individuals with DCM. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant ARVC (which can present with DCM) and autosomal recessive Carvajal syndrome. ACMG/AMP criteria applied: PVS1, PM2_Supporting. |
| Ambry Genetics | RCV003162642 | SCV003904658 | pathogenic | Cardiovascular phenotype | 2023-02-10 | criteria provided, single submitter | clinical testing | The c.1751delA pathogenic mutation, located in coding exon 14 of the DSP gene, results from a deletion of one nucleotide at nucleotide position 1751, causing a translational frameshift with a predicted alternate stop codon (p.E584Gfs*52). This variant has been detected in a cohort of patients from referral centers seeing patients for dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy diagnoses; however, details were limited (Smith ED et al. Circulation. 2020 Jun;141(23):1872-1884). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |