ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.2635_2636del (p.Leu879fs) (rs61753251)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000133357 SCV000191022 pathogenic not provided 2013-09-30 criteria provided, single submitter clinical testing The c.2635_2636delCT mutation in the CDKL5 gene has been reported previously in a female patient with early-onset epilepsy, acquired microcephaly, hand apraxia and hypotonia (Scala et al., 2005). The deletion causes a frameshift starting with codon Leucine 879, changes this amino acid to a Glutamic acid residue and creates a premature Stop codon at position 30 of the new reading frame, denoted p.Leu879GlufsX30. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay, and is consistent with the diagnosis of a CDKL5-related disorder. The variant is found in EPILEPSY panel(s).
Genetic Services Laboratory, University of Chicago RCV000145535 SCV000192624 pathogenic Early infantile epileptic encephalopathy 2 2013-02-08 criteria provided, single submitter clinical testing
Invitae RCV000229531 SCV000287890 pathogenic Early infantile epileptic encephalopathy 2; Angelman syndrome-like 2017-05-18 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotide from exon 18 of the CDKL5 mRNA (c.2635_2636delCT), causing a frameshift at codon 879. This creates a premature translational stop signal in exon 18 of the CDKL5 mRNA (p.Leu879Glufs*30). This variant has been reported in multiple females in the literature with Rett syndrome-like features, including epileptic encephalopathy (PMID: 15689447, 18790821, 22678952). In several of these individuals, the variant was found to be de novo. ClinVar contains an entry for this variant (Variation ID: 143809). Experimental evidence suggests that this variant escapes nonsense-mediated decay (PMID: 15689447) to produce a truncated protein product, which was shown to be mislocalized from the nucleus to the perinuclear region of the cytoplasm (PMID: 18790821). For these reasons, this variant has been classified as Pathogenic.
NeuroMeGen,Hospital Clinico Santiago de Compostela RCV000145535 SCV000693765 likely pathogenic Early infantile epileptic encephalopathy 2 2018-01-01 criteria provided, single submitter clinical testing
RettBASE RCV000169918 SCV000188368 pathogenic Atypical Rett syndrome 2014-03-13 no assertion criteria provided curation
RettBASE RCV000145535 SCV000222341 pathogenic Early infantile epileptic encephalopathy 2 2014-03-13 no assertion criteria provided curation

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