ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.745-2A>G

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002385124 SCV002674591 likely pathogenic Inborn genetic diseases 2017-12-27 criteria provided, single submitter clinical testing The c.745-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 9 in the CDKL5 gene. This nucleotide position is highly conserved in available vertebrate species. This variant has been observed in one female individual in the InterRett database (Fehr S et al. Eur. J. Hum. Genet., 2013 Mar;21:266-73). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Centre for Population Genomics, CPG RCV004725257 SCV005335143 likely pathogenic CDKL5 disorder 2024-09-09 criteria provided, single submitter curation This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as likely pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant is absent from gnomAD (PM2_Supporting). Has been observed in at least 1 individual with phenotypes consistent with CDKL5 disorder (PMID: 25657822).

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