ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.659T>C (p.Leu220Pro)

dbSNP: rs267608511
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000640488 SCV000762080 pathogenic Developmental and epileptic encephalopathy, 2; Angelman syndrome-like 2022-08-09 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CDKL5 function (PMID: 17993579, 22922712, 29420175). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CDKL5 protein function. ClinVar contains an entry for this variant (Variation ID: 143830). This missense change has been observed in individual(s) with Rett syndrome (PMID: 17993579, 22670135; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 220 of the CDKL5 protein (p.Leu220Pro).
Centre for Population Genomics, CPG RCV004724882 SCV005335139 likely pathogenic CDKL5 disorder 2024-09-06 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: This variant is absent from gnomAD (PM2_Supporting). This variant has been identified as a de novo occurrence in an individual with CDKL5 disorder without confirmation of paternity and maternity (PM6, PMID: 17993579). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). Well-established in vitro or in vivo functional studies supportive of a damaging effect on the protein function (PS3_supporting, PMID: 17993579).
RettBASE RCV000133381 SCV000188396 pathogenic Developmental and epileptic encephalopathy, 2 2014-03-13 no assertion criteria provided curation In vitro study shows mislocalisation of CDKL5 in the cytoplasm; In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = pathogenic (C65)

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