NM_001323289.2(CDKL5):c.533G>A (p.Arg178Gln) AND CDKL5 disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 25, 2021
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:: RCV001507061.12

Allele description [Variation Report for NM_001323289.2(CDKL5):c.533G>A (p.Arg178Gln)]

NM_001323289.2(CDKL5):c.533G>A (p.Arg178Gln)

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.533G>A (p.Arg178Gln)

Other names:

p.R178Q:CGG>CAG; NP_001310218.1:p.(Arg178Gln); NM_001323289.2(CDKL5):c.533G>A

HGVS:

NC_000023.11:g.18584332G>A
NG_008475.1:g.163728G>A
NM_001037343.2:c.533G>A
NM_001323289.2:c.533G>AMANE SELECT
NM_003159.3:c.533G>A
NP_001032420.1:p.Arg178Gln
NP_001310218.1:p.Arg178Gln
NP_003150.1:p.Arg178Gln
NP_003150.1:p.Arg178Gln
NC_000023.10:g.18602452G>A
NM_003159.2(CDKL5):c.533G>A
NM_003159.2:c.533G>A
O76039:p.Arg178Gln

Protein change:

R178Q

Links:

RettBASE (CDKL5): 132; UniProtKB: O76039#VAR_071103; dbSNP: rs267606715

NCBI 1000 Genomes Browser:

rs267606715

Molecular consequence:

NM_001037343.2:c.533G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323289.2:c.533G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003159.3:c.533G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001712029	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	reviewed by expert panel (ClinGen RettAS ACMG Specifications V1)	Pathogenic (Mar 25, 2021)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 24564546, 26482601, 29852413, 29190809, 21770923 Citation Link,
SCV005335287	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Pathogenic (Jul 12, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001712029

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RettAS ACMG Specifications V1)

Pathogenic
(Mar 25, 2021)

germline

curation

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV005335287

Centre for Population Genomics, CPG

criteria provided, single submitter

(McKnight et al. (Hum Mutat. 2022))

Pathogenic
(Jul 12, 2024)

germline

curation

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

Citation Link

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

Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients.

Zhao Y, Zhang X, Bao X, Zhang Q, Zhang J, Cao G, Zhang J, Li J, Wei L, Pan H, Wu X.

BMC Med Genet. 2014 Feb 25;15:24. doi: 10.1186/1471-2350-15-24.

PubMed [citation]

PMID:: 24564546
PMCID:: PMC3938974

High prevalence of genetic alterations in early-onset epileptic encephalopathies associated with infantile movement disorders.

Kobayashi Y, Tohyama J, Kato M, Akasaka N, Magara S, Kawashima H, Ohashi T, Shiraishi H, Nakashima M, Saitsu H, Matsumoto N.

Brain Dev. 2016 Mar;38(3):285-92. doi: 10.1016/j.braindev.2015.09.011. Epub 2015 Oct 23.

PubMed [citation]

PMID:: 26482601

See all PubMed Citations (6)

Details of each submission

From ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, SCV001712029.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (5)

Description

The p.Arg178Gln variant in CDKL5 has been reported in at least 4 de novo occurrences (biological parentage unconfirmed) in patients with CDKL5 disorder (PMID 26482601, 21770923, 29852413, 29190809, 24564546, 26482601) (PM6_very strong). The variant was present in the mosaic state in one patient, confirming its de novo nature (PMID 26482601) (PS2). The p.Arg178Gln variant in CDKL5 has been reported in at least 7 other individuals with CDKL5 disorder (PMID 26482601, 21770923, 29852413, 29190809, 24564546) (PS4). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 29100083, 22430159, 19793311, 18809835, 30182498) (PM5_strong). The p.Arg178Gln variant in CDKL5 is absent from gnomAD (PM2_supporting). In summary, the p.Arg178Gln variant in CDKL5 is classified as Pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PM6_very strong, PS2, PS4, PM5_strong, PM2_supporting).

#	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 Centre for Population Genomics, CPG, SCV005335287.1

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

Description

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 an individual with CDKL5 disorder with confirmed parental relationships (PS2) PMID 26482601 Has been observed in at least 5 individuals with phenotypes consistent with CDKL5 disorder (PS4). PMID 26482601, 21770923, 29852413, 29190809, 24564546, Variation ID: 94113 This variant has been identified as a de novo occurrence in>=4 individuals with CDKL5 disorder syndrome without confirmation of paternity and maternity (PM6_very strong). PMID 26482601, 21770923, 29852413, 29190809, 24564546, 26482601 This variant is absent from gnomAD (PM2_Supporting).

#	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: Nov 24, 2024

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