NM_001323289.2(CDKL5):c.872G>A (p.Cys291Tyr) AND CDKL5 disorder

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 25, 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:: RCV002281041.3

Allele description [Variation Report for NM_001323289.2(CDKL5):c.872G>A (p.Cys291Tyr)]

NM_001323289.2(CDKL5):c.872G>A (p.Cys291Tyr)

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.872G>A (p.Cys291Tyr)

Other names:

NM_001323289.2(CDKL5):c.872G>A

HGVS:

NC_000023.11:g.18598508G>A
NG_008475.1:g.177904G>A
NM_001037343.2:c.872G>A
NM_001323289.2:c.872G>AMANE SELECT
NM_003159.3:c.872G>A
NP_001032420.1:p.Cys291Tyr
NP_001310218.1:p.Cys291Tyr
NP_003150.1:p.Cys291Tyr
NP_003150.1:p.Cys291Tyr
NC_000023.10:g.18616628G>A
NM_003159.2:c.872G>A
O76039:p.Cys291Tyr

Protein change:

C291Y; CYS291TYR

Links:

RettBASE (CDKL5): 62; UniProtKB: O76039#VAR_058029; OMIM: 300203.0012; dbSNP: rs267606714

NCBI 1000 Genomes Browser:

rs267606714

Molecular consequence:

NM_001037343.2:c.872G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323289.2:c.872G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003159.3:c.872G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002569928	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	reviewed by expert panel (ClinGen RettAS ACMG Specifications V2)	Uncertain significance (Aug 25, 2022)	germline	curation	Citation Link,
SCV005335147	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Uncertain significance (Sep 9, 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

SCV002569928

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RettAS ACMG Specifications V2)

Uncertain significance
(Aug 25, 2022)

germline

curation

Citation Link,

SCV005335147

Centre for Population Genomics, CPG

criteria provided, single submitter

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

Uncertain significance
(Sep 9, 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

Recommendations by the ClinGen Rett/Angelman-like expert panel for gene-specific variant interpretation methods.

McKnight D, Bean L, Karbassi I, Beattie K, Bienvenu T, Bonin H, Fang P, Chrisodoulou J, Friez M, Helgeson M, Krishnaraj R, Meng L, Mighion L, Neul J, Percy A, Ramsden S, Zoghbi H, Das S.

Hum Mutat. 2022 Aug;43(8):1097-1113. doi: 10.1002/humu.24302. Epub 2021 Dec 2.

PubMed [citation]

PMID:: 34837432
PMCID:: PMC9135956

Details of each submission

From ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, SCV002569928.1

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

Description

The p.Cys291Tyr variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with severe early-onset encephalopathy (PMID 18809835) (PM6). The p.Cys291Tyr variant in CDKL5 is absent from gnomAD (PM2_Supporting). The p.Cys291Tyr variant has been observed in at least 1 other individual with CDKL5-related disorder (PMID 18809835, PMID 25657822) (PS4_Supporting). In summary, the p.Cys291Tyr variant in CDKL5 is classified as a variant of unknown significance based on the ACMG/AMP criteria (PM6, PM2_Supporting, PS4_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, SCV005335147.1

#	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 a variant of uncertain significance. At least the following criteria are met: This variant has been identified as a de novo occurrence in an individual with CDKL5 disorder without confirmation of paternity and maternity (PM6, PMID: 18809835). Has been observed in at least 2 individuals with phenotypes consistent with CDKL5 disorder (PS4_Supporting, PMID: 25657822, PMID: 18809835). 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: Oct 8, 2024

ClinVar

Relating variation to medicine