ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.6466dup (p.Arg2156fs) (rs1554108859)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478639 SCV000567336 pathogenic not provided 2015-07-27 criteria provided, single submitter clinical testing Although the c.6466dupA duplications in the DSP gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Arginine 2156, changing it to a Lysine, and creating apremature stop codon at position 9 of the new reading frame, denoted p.Arg2156LysfsX9. This duplication isexpected to result in an abnormal, truncated protein product with the last 716 correct amino acids beingreplaced by 8 incorrect amino acids. Other frameshift variants in the DSP gene have been reported inHGMD in association with cardiomyopathy (Stenson P et al., 2014). Furthermore, the c.6466dupA duplicationwas not observed in approximately 6,500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.6466dupA in the DSP gene is interpreted as a pathogenic variant.
Invitae RCV000699748 SCV000828473 pathogenic Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-09-05 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the DSP gene (p.Arg2156Lysfs*9). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 716 amino acids of the DSP protein. 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: 419496). Different truncations (p.Arg2166*, p.Ser2168Argfs*18, p.Gly2414*) that lie downstream of this variant have been determined to be pathogenic (PMID: 27532257, 23671136, Invitae). This suggests that deletion of this region of the DSP protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

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