ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.464-2A>G

dbSNP: rs267608480
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002336287 SCV002639898 pathogenic Inborn genetic diseases 2018-02-19 criteria provided, single submitter clinical testing The c.464-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 7 in the CDKL5 gene. This mutation (denoted as IVS7-2A>G) was first described in an infant with microcephaly, severe developmental delay, failure to thrive, hand stereotypies, variable tone, and dysmorphic facial features, who met clinical criteria for Rett syndrome but whose features more closely resembled severe epileptic encephalopathy. Amplification of cDNA revealed 2 different RT-PCR products, and sequencing of the smaller product was consistent with loss of exon 8 (coding exon 7) (Evans JC et al. Eur. J. Hum. Genet., 2005 Oct;13:1113-20). This mutation has also been observed in an individual with early onset epileptic encephalopathy (Carvill GL et al. Nat. Genet., 2013 Jul;45:825-30). In addition to the clinical data presented in the literature, 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 a disease-causing mutation.
Centre for Population Genomics, CPG RCV004724908 SCV005335235 pathogenic CDKL5 disorder 2024-09-20 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 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 v4 (PM2_Supporting). Has been observed in at least 2 individuals with phenotypes consistent with CDKL5 disorder (PS4_Supporting). PubMed: 16015284‚ 23708187, Variation ID: 156090.
RettBASE RCV000144137 SCV000189214 not provided not provided flagged submission not provided
RettBASE RCV000170046 SCV000222354 pathogenic Developmental and epileptic encephalopathy, 2 2014-03-13 no assertion criteria provided curation Leads to exon 8 skipping, r.464_554del

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