NM_001323289.2(CDKL5):c.2842C>T (p.Arg948Ter) AND CDKL5 disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 1, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002281117.5

Allele description [Variation Report for NM_001323289.2(CDKL5):c.2842C>T (p.Arg948Ter)]

NM_001323289.2(CDKL5):c.2842C>T (p.Arg948Ter)

Gene:

CDKL5:cyclin dependent kinase like 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp22.13

Genomic location:

Preferred name:

NM_001323289.2(CDKL5):c.2842C>T (p.Arg948Ter)

Other names:

NM_001323289.2(CDKL5):c.2842C>T; p.Arg948Ter

HGVS:

NC_000023.11:g.18628716C>T
NG_008475.1:g.208112C>T
NM_001037343.2:c.2713+129C>T
NM_001323289.2:c.2842C>TMANE SELECT
NM_003159.3:c.2713+129C>T
NP_001310218.1:p.Arg948Ter
NC_000023.10:g.18646836C>T
NM_001323289.1:c.2842C>T
NM_003159.2:c.2713+129C>T

Protein change:

R948*

Links:

dbSNP: rs1555955296

NCBI 1000 Genomes Browser:

rs1555955296

Molecular consequence:

NM_001037343.2:c.2713+129C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_003159.3:c.2713+129C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001323289.2:c.2842C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: CDKL5 disorder
Identifiers:: MONDO: MONDO:0100039; MedGen: CN296942

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002569929	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	reviewed by expert panel (ClinGen RettAS ACMG Specifications V2)	Pathogenic (Sep 1, 2022)	germline	curation	Citation Link,
SCV003922279	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 2, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002569929

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RettAS ACMG Specifications V2)

Pathogenic
(Sep 1, 2022)

germline

curation

Citation Link,

SCV003922279

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 2, 2023)

germline

curation

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, SCV002569929.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV003922279.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 28, 2024

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