ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.5321_5322AG[3] (p.Glu1776fs) (rs1394836623)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657566 SCV000779303 likely pathogenic not provided 2018-05-23 criteria provided, single submitter clinical testing Although the c.5327_5330delAGAG likely pathogenic variant in the DSP gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon glutamic acid 1776, changing it to a glycine, and creating a premature stop codon at position 4 of the new reading frame, denoted p.Glu1776GlyfsX4. This variant is expected to result in an abnormal, truncated protein product. Several other frameshift variants in the DSP gene have been reported downstream of the c.5327_5330delAGAG variant in the Human Gene Mutation Database in association with DSP-related disorders (Stenson et al., 2014). Furthermore, the c.5327_5330delAGAG variant has not been observed in large population cohorts (Lek et al., 2016).
Invitae RCV000801235 SCV000941004 pathogenic Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-12-10 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the DSP gene (p.Glu1776Glyfs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1096 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: 545955). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant disrupts the C-terminus of the DSP protein. Other variant(s) that disrupt this region (p.Arg1951*, p.Arg2166*, p.Ser2168Argfs*18) have been determined to be pathogenic (PMID: 27532257, 23671136, 28527814, 21859740, 11063735, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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