X-18628716-C-T

Position:

• chrX-18628716-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2_Supporting PS2 PVS1

This summary comes from the ClinGen Evidence Repository: The p.Arg948Ter variant in CDKL5 is absent from gnomAD (PM2_Supporting). The p.Arg948Ter variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with features of CDKL5-associated disorder (PMID 32366967; internal database) (PS2_Very Strong). The p.Arg948Ter variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. While loss-of-function variants are commonly observed in affected individuals in this gene, there is a paucity of these variants in this region of the gene to date (PVS1). In summary, the p.Arg948Ter variant in CDKL5 is classified as pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PM2_Supporting, PS2_Very Strong, PVS1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA412369187/MONDO:0100039/016

• Frequency: Genomes: not found (cov: 21)
• Consequence: CDKL5 NM_001323289.2 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 1.35

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.2842C>T	p.Arg948Ter	stop_gained	18/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.2713+129C>T		intron_variant			NP_001032420.1
CDKL5	NM_003159.3	c.2713+129C>T		intron_variant			NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.2842C>T	p.Arg948Ter	stop_gained	18/18	1	NM_001323289.2	ENSP00000485244	P1
CDKL5	ENST00000379989.6	c.2713+129C>T		intron_variant		1		ENSP00000369325
CDKL5	ENST00000379996.7	c.2713+129C>T		intron_variant		1		ENSP00000369332
CDKL5	ENST00000674046.1	c.2965C>T	p.Arg989Ter	stop_gained	19/19			ENSP00000501174

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

CDKL5 disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The hemizygous p.Arg948Ter variant in CDKL5 was identified by our study in one individual with infantile-onset epilepsy (Broad Institute Rrae Genomes Project). Trio genome analysis showed this variant to be de novo. The p.Arg948Ter variant in CDKL5 has been previously reported in two unrelated individuals with developmental and epileptic encephalopathy 2 (PMID: 32366967, ClinVar SCV002569929.1). This variant was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 489299) and has been interpreted as pathogenic by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, NIH Undiagnosed Diseases Network, and GeneDx. This nonsense variant leads to a premature termination codon at position 948. This alteration occurs within the terminal 50 bases of the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the CDKL5 gene is an established disease mechanism in X-linked developmental and epileptic encephalopathy 2. In summary, this variant meets criteria to be classified as pathogenic for developmental and epileptic encephalopathy 2. ACMG/AMP Criteria applied: PVS1_Strong, PS2, PM2_Supporting (Richards 2015). -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Sep 01, 2022	The p.Arg948Ter variant in CDKL5 is absent from gnomAD (PM2_Supporting). The p.Arg948Ter variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with features of CDKL5-associated disorder (PMID 32366967; internal database) (PS2_Very Strong). The p.Arg948Ter variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. While loss-of-function variants are commonly observed in affected individuals in this gene, there is a paucity of these variants in this region of the gene to date (PVS1). In summary, the p.Arg948Ter variant in CDKL5 is classified as pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PM2_Supporting, PS2_Very Strong, PVS1). -

Developmental and epileptic encephalopathy, 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Sep 05, 2018

This variant was reported by the clinical laboratory as pathogenic in July 2018. Previous testing at a different laboratory in October 2016 did not report the variant because it was only in a coding region on transcript NM_001323289.1 and not the other isoforms of CDKL5, including the canonical transcript. This transcript was added to NCBI RefSeq database in April 2016 but had not yet been curated into their annotation set and so was not included in their analysis in October 2016. This variant is present in the NM_001323289.1 transcript, which is confirmed to be expressed in the brain in both humans and mice. Our patient's variant is located in exon 17, which is longer in this alternative transcript than in the canonical transcript. Earlier this year, a male patient with intractable seizures was reported to have a de novo frameshift mutation within the same exon 17 in the same transcript NM_001323289.1 (PMID: 29444904). -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 08, 2020

The p.Arg948X variant in CDKL5 has been reported in the hemizygous state in a young male with infantile spasms, atonic seizures, developmental delays, and regression (Schoch et al, 2020) and in the heterozygous state in a young female with infantile spasms, epilepsy, and developmental delay (Broad Institute Rare Genomes Project). In both individuals the variant was found to be de novo through trio whole genome sequence analysis. This variant has also been reported by a clinical laboratory in ClinVar (Variation ID 482247) and is absent from large population studies. This variant is present in the NM_001323289.2 transcript, which is confirmed to be expressed in the brain in both humans and mice (Hector RD et al 2016). This nonsense variant leads to a premature termination codon at position 948. This alteration occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. However, identification of other de novo truncating variants in this region suggest the region is critical for protein function. In summary, this variant meets criteria to be classified as pathogenic for X-linked dominant early infantile epileptic encephalopathy based on case observations, de novo occurrence, absence from large population studies, and predicted impact on protein. ACMG/AMP Criteria applied: PS2, PVS1_Strong, PM2_Supporting. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 25, 2021

Nonsense variant predicted to result in protein truncation as the last 13 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed at significant frequency in large population cohorts (Lek 2006).; This variant is associated with the following publications: (PMID: 31814998, 32366967, 27535533) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Pathogenic	35
DANN	Benign	0.81
FATHMM_MKL	Benign	0.74	D
MutationTaster	Benign	1.0	D;D
Vest4		0.39
GERP RS		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555955296; hg19: chrX-18646836;