ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.38T>C (p.Phe13Ser)

dbSNP: rs1922605766
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel RCV002281167 SCV002569949 likely pathogenic CDKL5 disorder 2022-09-01 reviewed by expert panel curation The p.Phe13Ser variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with CDKL5 disorder (internal database) and as a de novo occurrence (biological parentage unconfirmed) in an individual with CDKL5 disorder (PMID 31313283) (PS2). The p.Phe13Ser variant in CDKL5 is present in an individual with a clinical phenotype suggestive of CDKL5 disorder (internal database) (PP4). The p.Phe13Ser variant in CDKL5 is absent from gnomAD (PM2_Supporting). In summary, the p.Phe13Ser variant in CDKL5 is classified as likely pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PS2, PP4, PM2_Supporting).
Labcorp Genetics (formerly Invitae), Labcorp RCV001204295 SCV001375495 pathogenic Developmental and epileptic encephalopathy, 2; Angelman syndrome-like 2021-10-22 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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: 929426). This missense change has been observed in individual(s) with clinical features of CDKL5-related conditions (PMID: 22872100, 31313283; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with serine at codon 13 of the CDKL5 protein (p.Phe13Ser). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and serine.
Centre for Population Genomics, CPG RCV002281167 SCV005335177 likely pathogenic CDKL5 disorder 2024-07-04 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 has been identified as a de novo occurrence in an individual with CDKL5 disorder with confirmed parental relationships (PS2, ClinGen Rett and Angelman-like Disorders VCEP). It has been identified as a de novo occurrence in an individual with CDKL5 disorder without confirmation of paternity and maternity (PM6, PMID: 31313283). This variant is absent from gnomAD (PM2_Supporting).
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV001194616 SCV001364273 pathogenic Developmental and epileptic encephalopathy, 2 2020-02-19 no assertion criteria provided clinical testing

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