ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.2437-1G>C (rs1057517903)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413527 SCV000491020 likely pathogenic not provided 2016-02-12 criteria provided, single submitter clinical testing Although the c.2437-1 G>C variant has not been reported as a pathogenic variant or as a benign variant to our knowledge, this variant destroys the canonical splice acceptor site in intron 17 and is predicted to cause abnormal gene splicing. The variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site variants in the DSP gene have been reported in HGMD in association with ARVC (Stenson P et al., 2014). Furthermore, the c.2437-1 G>C variant was not observed in approximately 6500 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.2437-1 G>C in the DSP gene is interpreted as a likely pathogenic variant.
Invitae RCV000823724 SCV000964594 likely pathogenic Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2019-07-26 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 17 of the DSP gene. It is expected to disrupt RNA splicing and likely results 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. ClinVar contains an entry for this variant (Variation ID: 372644). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825635 SCV000966998 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2018-05-04 criteria provided, single submitter clinical testing The c.2437-1G>C variant in DSP has not been previously reported in individuals w ith cardiomyopathy and was absent from large population studies. It has been rep orted in ClinVar (Variation ID: 372644). This variant occurs in the invariant re gion (+/- 1,2) of the splice consensus sequence and is predicted to cause altere d splicing leading to an abnormal or absent protein. Other splice site variants have been reported in individuals with ARVC (HGMD database) and many splice vari ants lead to absent protein (loss of function), which is an established mechanis m of disease for DSP. In summary, although additional studies are required to fu lly establish its clinical significance, the c.2437-1G>C variant is likely patho genic. ACMG/AMP criteria applied: PVS1, PM2.

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