Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000523503 | SCV000621059 | likely pathogenic | not provided | 2022-02-18 | criteria provided, single submitter | clinical testing | Has been reported in an individual identified as part of the eMERGE study (Carruth et al., 2019; Carruth et al., 2021); Not observed in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 33684294, 31447099) |
| Laboratory for Molecular Medicine, |
RCV000825580 | SCV000966920 | likely pathogenic | Arrhythmogenic right ventricular cardiomyopathy | 2018-07-18 | criteria provided, single submitter | clinical testing | The p.Arg1628fs variant in DSP has not been previously reported in individuals w ith arrhythmogenic right ventricular cardiomyopathy (ARVC) and was absent from l arge population studies, though the ability of these studies to accurately detec t indels may be limited. This variant has been reported in ClinVar (Variation ID : 452266). This variant is located within exon 23 of DSP which undergoes alterna tive splicing resulting in two isoforms: one with a shorter and one with a longe r form of this exon. This variant is only located in the coding region of the lo nger isoform. In that transcript, this variant is predicted to cause a frameshif t, which alters the protein?s amino acid sequence beginning at position 1628 and leads to a premature termination codon 17 amino acids downstream. This alterati on is then predicted to lead to a truncated or absent protein. Loss-of-function variants in the longer form of exon 23 have been observed in individuals with AR VC and/or DCM, suggesting that loss-of-function variants in this region are like ly to be disease causing (LMM data). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg1628fs variant is likely pathogenic. ACMG/AMP criteria applied: PVS1, PM2. |
| Ambry Genetics | RCV002329242 | SCV002633867 | pathogenic | Cardiovascular phenotype | 2021-08-06 | criteria provided, single submitter | clinical testing | The c.4882_4886delAGGAGinsTTCT pathogenic mutation, located in coding exon 23 of the DSP gene, results from the deletion of 5 nucleotides and insertion of 4 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.R1628Ffs*17). 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. As such, this alteration is interpreted as a disease-causing mutation. |
| Fulgent Genetics, |
RCV002506278 | SCV002815918 | likely 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 | 2021-10-26 | criteria provided, single submitter | clinical testing |