rs267608501

Variant names:

• chrX-18587986-C-T
• rs267608501
• NM_001323289.2:c.587C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001323289.2(CDKL5):​c.587C>T​(p.Ser196Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S196S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 7.57
• Publications: 11 publications found

Genes affected

CDKL5 (HGNC:11411): (cyclin dependent kinase like 5) This gene is a member of Ser/Thr protein kinase family and encodes a phosphorylated protein with protein kinase activity. Mutations in this gene have been associated with X-linked infantile spasm syndrome (ISSX), also known as X-linked West syndrome, and Rett syndrome (RTT). Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]

CDKL5 Gene-Disease associations (from GenCC):

• CDKL5 disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• precocious puberty

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001323289.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant X-18587986-C-T is Pathogenic according to our data. Variant chrX-18587986-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 143827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323289.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	NM_001323289.2	MANE Select	c.587C>T	p.Ser196Leu	missense	Exon 9 of 18	NP_001310218.1
	CDKL5	NM_001037343.2		c.587C>T	p.Ser196Leu	missense	Exon 10 of 22	NP_001032420.1
	CDKL5	NM_003159.3		c.587C>T	p.Ser196Leu	missense	Exon 9 of 21	NP_003150.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.587C>T	p.Ser196Leu	missense	Exon 9 of 18	ENSP00000485244.1
	CDKL5	ENST00000379989.6	TSL:1	c.587C>T	p.Ser196Leu	missense	Exon 10 of 22	ENSP00000369325.3
	CDKL5	ENST00000379996.7	TSL:1	c.587C>T	p.Ser196Leu	missense	Exon 9 of 21	ENSP00000369332.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:5

Mar 14, 2017

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 13, 2014

RettBASE

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = pathogenic (C65)

Mar 20, 2025

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.69 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.93 (> 0.75, sensitivity 0.96 and precision 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000143827 / PMID: 20397747). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 22872100, 31791873). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 20397747). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

May 04, 2022

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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).

not provided Pathogenic:5

Sep 15, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 19, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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)

CDKL5 disorder Pathogenic:1

Sep 05, 2024

Centre for Population Genomics, CPG

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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: This variant has been identified as a de novo occurrence in at least 2 individuals with CDKL5 disorder, without confirmation of paternity and maternity (PM6_Strong, PMID: 20397747, PMID: 33436160, ClinVar Variation ID: 143827). Has been observed in at least 5 individuals with phenotypes consistent with CDKL5 disorder (PS4, PMID: 31791873, 31791873, ClinVar Variation ID: 143827). This variant is absent from gnomAD (PM2_Supporting).

Epileptic encephalopathy Pathogenic:1

Nov 16, 2016

Neurogenetics Laboratory - MEYER, AOU Meyer

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Pathogenic:1

Dec 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.96		Loss of catalytic residue at S196 (P = 0.0265)
MVP		0.94
MPC		2.1
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.98
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs267608501; hg19: chrX-18606106; COSMIC: COSV66112168;