Submissions for variant NM_001323289.2(CDKL5):c.587C>T (p.Ser196Leu)

dbSNP: rs267608501

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000145544	SCV000192637	pathogenic	Developmental and epileptic encephalopathy, 2	2013-02-08	criteria provided, single submitter	clinical testing
Neurogenetics Laboratory - MEYER, AOU Meyer	RCV000416982	SCV000494535	pathogenic	Epileptic encephalopathy	2016-11-16	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000431821	SCV000511415	pathogenic	not provided	2016-09-15	criteria provided, single submitter	clinical testing
Invitae	RCV000812193	SCV000952498	pathogenic	Developmental and epileptic encephalopathy, 2; Angelman syndrome-like	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 196 of the CDKL5 protein (p.Ser196Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 20397747; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143827). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000145544	SCV001428608	pathogenic	Developmental and epileptic encephalopathy, 2	2017-03-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000431821	SCV001811448	pathogenic	not provided	2023-01-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22872100, 22670135, 35153983, 22779007, 20397747, 25657822, 22264704, 31791873, 34489640, 33436160, 33047306)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000145544	SCV002507068	likely pathogenic	Developmental and epileptic encephalopathy, 2	2022-05-04	criteria provided, single submitter	curation	The heterozygous p.Ser196Leu variant in CDKL5 was identified by our study in 1 individual with early infantile epileptic encephalopathy 2. Trio exome analysis showed this variant to be de novo, and this variant is also assumed de novo in 3 individuals in the literature, but maternity and paternity have not been confirmed (PMID: 20397747, 33436160). The variant has been reported in at least 8 individuals of unknown ethnicity with early infantile epileptic encephalopathy 2 (PMID: 20397747, 31791873, 22872100, 22264704, 33436160, 24375629), but was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 143827) as pathogenic by Genetic Services Laboratory, University of Chicago, Neurogenetics Laboratory - MEYER, AOU Meyer, and Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, and as likely pathogenic by Invitae and RettBASE. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS2, PS4_moderate, PM2 (Richards 2015).
RettBASE	RCV000145544	SCV000188393	likely pathogenic	Developmental and epileptic encephalopathy, 2	2014-03-13	no assertion criteria provided	curation	In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = pathogenic (C65)
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000431821	SCV001930972	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000431821	SCV001959800	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000431821	SCV002035960	pathogenic	not provided		no assertion criteria provided	clinical testing