ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.4882_4886delinsTTCT (p.Arg1628fs) (rs1554108410)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523503 SCV000621059 likely pathogenic not provided 2017-09-15 criteria provided, single submitter clinical testing The c.4882_4886delAGGAGinsTTCT variant in the DSP gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.4882_4886delAGGAGinsTTCT variant causes a frameshift starting with codon Arginine 1628, changes this amino acid to a Phenylalanine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Arg1628phefsX17. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.4882_4886delAGGAGinsTTCT variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.4882_4886delAGGAGinsTTCT as a likely pathogenic variant.
Invitae RCV000641798 SCV000763448 pathogenic Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-12-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1628Phefs*17) in the DSP gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 452266). Loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized 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.

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