ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.3735_3741dup (p.Asp1248fs) (rs1554108152)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181367 SCV000233668 pathogenic not provided 2016-12-08 criteria provided, single submitter clinical testing The c.3735_3741dupAAATCGA pathogenic variant in the DSP gene has been previously reported in one individual with DCM and one individual with ARVC (Walsh et al., 2016). This variant causes a shift in reading frame starting at codon Aspartic acid 1248, changing it to a Lysine, and creating a premature stop codon at position 7 of the new reading frame, denoted p.Asp1248LysfsX7. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Multiple other downstream frameshift variants in the DSP gene have been reported in HGMD in association with DSP-related disorders (Stenson et al., 2014). Furthermore, the c.3735_3741dupAAATCGA variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.3735_3741dupAAATCGA in the DSP gene is interpreted as a pathogenic variant.
Invitae RCV000470407 SCV000543197 pathogenic Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-09-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp1248Lysfs*7) in the DSP gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs756613460, ExAC 0.002%). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 199923). Loss-of-function variants in DSP are known to be pathogenic (PMID: 24503780, 20716751). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000603827 SCV000712860 likely pathogenic Primary dilated cardiomyopathy; Arrhythmogenic right ventricular cardiomyopathy 2017-02-02 criteria provided, single submitter clinical testing The p.Asp1248fs variant in DSP has not been previously reported in individuals w ith cardiomyopathy, but has been identified in 1/66014 European chromosomes by t he Exome Aggregation Consortium (ExAC,; dbSNP rs7 94728144). 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 1248 and leads to a premature termination codon 7 amino acids downstream. This alteratio n is then predicted to lead to a truncated or absent protein. Loss-of-function v ariants in the longer form of exon 23 have been observed in 6 individuals with A RVC and/or DCM, suggesting that loss-of-function variants in this region are lik ely to be disease causing (LMM data). In summary, although additional studies ar e required to fully establish its clinical significance, the p.Asp1248fs variant is likely pathogenic.
Ambry Genetics RCV000618361 SCV000736860 pathogenic Cardiovascular phenotype 2017-07-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Functionally-validated splicing mutation

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