NM_001323289.2:c.199C>T

Variant names:

• chrX-18575407-C-T
• rs267608437
• NM_001323289.2:c.199C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2_Supporting PP3

This summary comes from the ClinGen Evidence Repository: The p.Leu67Phe variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Leu67Phe variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In summary, the p.Leu67Phe variant in CDKL5 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM2_supporting, PP3). (CDKL5 Specifications v.4.1; curation approved on [5/7/2025]) LINK:https://erepo.genome.network/evrepo/ui/classification/CA170464/MONDO:0100039/034

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:3
• Conservation: PhyloP100: 4.95
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.199C>T	p.Leu67Phe	missense_variant	Exon 5 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.199C>T	p.Leu67Phe	missense_variant	Exon 6 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.199C>T	p.Leu67Phe	missense_variant	Exon 5 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.199C>T	p.Leu67Phe	missense_variant	Exon 5 of 18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

CDKL5 disorder Uncertain:2

Jul 15, 2024

Centre for Population Genomics, CPG

Significance: Uncertain significance

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 variant of uncertain significance. At least the following criteria are met: This variant is absent from gnomAD (PM2_Supporting). -

May 07, 2025

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The p.Leu67Phe variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Leu67Phe variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In summary, the p.Leu67Phe variant in CDKL5 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM2_supporting, PP3). (CDKL5 Specifications v.4.1; curation approved on [5/7/2025]) -

Rett syndrome Pathogenic:1

Apr 26, 2016

RettBASE

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Developmental and epileptic encephalopathy, 2 Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 67 of the CDKL5 protein (p.Leu67Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDKL5-related conditions. ClinVar contains an entry for this variant (Variation ID: 143791). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;.;T;.;.;.
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	.;D;D;D;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.049	D
MutationAssessor	Benign	2.0	M;.;.;M;.;.;M
PhyloP100		5.0
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.7	D;.;.;D;.;.;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.020	D;.;.;D;.;.;.
Sift4G	Uncertain	0.013	D;.;.;D;T;D;D
Polyphen		1.0	D;.;.;D;.;.;.
Vest4		0.78
MutPred		0.76		Gain of methylation at K68 (P = 0.0748);Gain of methylation at K68 (P = 0.0748);Gain of methylation at K68 (P = 0.0748);Gain of methylation at K68 (P = 0.0748);Gain of methylation at K68 (P = 0.0748);Gain of methylation at K68 (P = 0.0748);Gain of methylation at K68 (P = 0.0748);
MVP		0.95
MPC		2.6
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.92
gMVP		0.95
Mutation Taster		=24/76	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: rs267608437; hg19: chrX-18593527;