X-18575423-T-C

Variant names:

• chrX-18575423-T-C
• rs62641235
• NM_001323289.2:c.215T>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3_Supporting PM6 PP3 PM2_Supporting PM5_Strong PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The p.Ile72Thr variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with CDKL5 disease (PMID 19396824, 19241098) (PM6). The p.Ile72Thr variant in CDKL5 has been reported in at least 3 other individuals with CDKL5 disease (PMID 19396824, 19241098, 25657822, ClinVar) (PS4_moderate). The p.Ile72Thr variant in CDKL5 is absent from gnomAD (PM2). Multiple likely pathogenic missense variants have been previously identified within this codon (p.Ile72Asn; p.Ile72Met) which indicates that this residue is critical to the function of the protein (PMID 28074849, 27779742, 16015284) (PM5_strong). Phosphoproteomic screening of the cellular substrates of CDKL5 (MAP1S, CEP131 and DLG5) has shown that the p.Ile72Thr variant impacts protein function (PMID 30266825) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own(PP3). In summary, the p.Ile72Thr variant in CDKL5 is classified as Pathogenic for CDKL5 disease based on the ACMG/AMP criteria (PM5_strong, PM6, PS4_moderate, PS3_supporting, PM2_supporting, PP3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA121523/MONDO:0100039/016

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 8.02
• Publications: 7 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 11 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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.215T>C	p.Ile72Thr	missense_variant	Exon 5 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.215T>C	p.Ile72Thr	missense_variant	Exon 6 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.215T>C	p.Ile72Thr	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.215T>C	p.Ile72Thr	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: 0.0000517 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

CDKL5 disorder Pathogenic:2

Jul 23, 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: >=2 different missense variants in the same codon have been classified as pathogenic (PM5_Strong). Has been observed in at least 3 individuals with phenotypes consistent with CDKL5 disorder (PS4_Moderate). This variant has been identified as a de novo occurrence in an individual with CDKL5 disorder without confirmation of paternity and maternity (PM6). This variant is absent from gnomAD v4 (PM2_Supporting). -

Mar 26, 2021

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The p.Ile72Thr variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with CDKL5 disease (PMID 19396824, 19241098) (PM6). The p.Ile72Thr variant in CDKL5 has been reported in at least 3 other individuals with CDKL5 disease (PMID 19396824, 19241098, 25657822, ClinVar) (PS4_moderate). The p.Ile72Thr variant in CDKL5 is absent from gnomAD (PM2). Multiple likely pathogenic missense variants have been previously identified within this codon (p.Ile72Asn; p.Ile72Met) which indicates that this residue is critical to the function of the protein (PMID 28074849, 27779742, 16015284) (PM5_strong). Phosphoproteomic screening of the cellular substrates of CDKL5 (MAP1S, CEP131 and DLG5) has shown that the p.Ile72Thr variant impacts protein function (PMID 30266825) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own(PP3). In summary, the p.Ile72Thr variant in CDKL5 is classified as Pathogenic for CDKL5 disease based on the ACMG/AMP criteria (PM5_strong, PM6, PS4_moderate, PS3_supporting, PM2_supporting, PP3). -

not provided Pathogenic:2

Mar 10, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19396824, 19241098, 25657822, 29655203, 22779007, 22670135, 31313283, 31302675) -

Rett syndrome Pathogenic:1

Apr 26, 2016

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Developmental and epileptic encephalopathy, 2 Pathogenic:1

May 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Seizure Pathogenic:1

Mar 06, 2025

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 08, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ile72 amino acid residue in CDKL5. Other variant(s) that disrupt this residue have been observed in individuals with CDKL5-related conditions (PMID: 28074849, 27779742, 16015284), which suggests that this may be a clinically significant amino acid residue. This variant has been reported to affect CDKL5 protein function (PMID: 30266825). This variant has been observed in individual(s) with early infantile epileptic encephalopathy/West syndrome (PMID: 19396824). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11503). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 72 of the CDKL5 protein (p.Ile72Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;.;T;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	.;D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Uncertain	0.040	D
MutationAssessor	Uncertain	2.6	M;.;.;M;.;M
PhyloP100		8.0
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.9	D;.;.;D;.;.
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;.;.;D;.;.
Sift4G	Pathogenic	0.0010	D;.;.;D;D;D
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.97
MutPred		0.94		Gain of disorder (P = 0.0276);Gain of disorder (P = 0.0276);Gain of disorder (P = 0.0276);Gain of disorder (P = 0.0276);Gain of disorder (P = 0.0276);Gain of disorder (P = 0.0276);
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.99
Mutation Taster		=13/87	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: rs62641235; hg19: chrX-18593543;