ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.4037_4041del (p.Asn1346fs) (rs1561698362)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000691128 SCV000818871 pathogenic Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-06-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn1346Thrfs*3) 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. 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 RCV000825581 SCV000966921 likely pathogenic Cardiomyopathy 2018-07-03 criteria provided, single submitter clinical testing The p.Asn1346ThrfsX3 variant in DSP has not been previously reported in individu als with cardiomyopathy and was absent from large population studies. This varia nt is located within exon 23 of DSP which undergoes alternative splicing resulti ng in two isoforms: one with a shorter and one with a longer form of this exon. This variant is only located in the coding region of the longer isoform. In that transcript, this variant is predicted to cause a frameshift, which alters the p rotein?s amino acid sequence beginning at position 1346 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted t o lead to a truncated or absent protein. Loss-of-function variants in the longer form of exon 23 have been observed in individuals with ARVC and/or DCM, suggest ing that loss-of-function variants in this region are likely to be disease causi ng (LMM data). In summary, although additional studies are required to fully est ablish its clinical significance, the p.Asn1346ThrfsX3 variant is likely pathoge nic. ACMG/AMP Criteria applied: PVS1, PM2.

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