ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.4305_4309del (p.Thr1436fs) (rs1554108287)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000548373 SCV000639739 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 8 2017-04-27 criteria provided, single submitter clinical testing This sequence change deletes 5 nucleotides from exon 23 of the DSP mRNA (c.4305_4309delCACTG), causing a frameshift at codon 1436. This creates a premature translational stop signal (p.Thr1436Leufs*2) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in DSP are known to be pathogenic (PMID: 16061754, 20716751, 24503780). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000603257 SCV000731687 likely pathogenic Primary dilated cardiomyopathy; Arrhythmogenic right ventricular cardiomyopathy 2017-06-08 criteria provided, single submitter clinical testing The p.Thr1436fs variant in DSP has not been previously reported in individuals w ith cardiomyopathy or large population studies. This variant is located within e xon 23 of DSP which undergoes alternative splicing resulting in two isoforms: on e with a shorter and one with a longer form of this exon. This variant is only l ocated in the coding region of the longer isoform. In that transcript, this vari ant is predicted to cause a frameshift, which alters the protein?s amino acid se quence beginning at position 1436 and leads to a premature termination codon 2 a mino acids downstream. This alteration is then predicted to cause a truncated or absent protein. Loss-of-function variants in the longer form of exon 23 have be en observed in individuals with ARVC and/or DCM, suggesting that loss-of-functio n variants in this region are likely to be disease causing (LMM data). In summar y, although additional studies are required to fully establish its clinical sign ificance, the p.Thr1436fs variant is likely pathogenic.

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