ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.404-2A>G (rs587783080)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000144742 SCV000190952 pathogenic not provided 2017-03-15 criteria provided, single submitter clinical testing The c.404-2 A>G splice site variant in the CDKL5 gene destroys the canonical splice acceptor site in intron 6 and is predicted to cause abnormal gene splicing, either leading to 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. Although this pathogenic variant has not been previously reported to our knowledge, other nearby splice site variants have been reported in association with CDKL5-related disorders (RettBASE).
Invitae RCV001215542 SCV001387293 pathogenic Early infantile epileptic encephalopathy 2; Angelman syndrome-like 2019-05-23 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 6 of the CDKL5 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). Disruption of this splice site has been observed in individuals affected with clinical features of epileptic encephalopathy, in at least one of whom it was found de novo (PMID: 27081548, 16611748, 29655203). ClinVar contains an entry for this variant (Variation ID: 156599). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDKL5 are known to be pathogenic (PMID: 22872100). For these reasons, this variant has been classified as Pathogenic.

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