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

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 15, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001203327.8

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:: Developmental and epileptic encephalopathy, 2 (DEE2)
Synonyms:: INFANTILE SPASM SYNDROME, X-LINKED 2; Early infantile epileptic encephalopathy 2
Identifiers:: MONDO: MONDO:0010396; MedGen: C4750718; Orphanet: 1934; Orphanet: 3451; OMIM: 300672

Name:: Angelman syndrome-like
Identifiers:: MedGen: CN128785

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001374486	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 15, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18809835, 25657822, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001374486

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 15, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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	clinical testing

Citations

PubMed

CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy.

Elia M, Falco M, Ferri R, Spalletta A, Bottitta M, Calabrese G, Carotenuto M, Musumeci SA, Lo Giudice M, Fichera M.

Neurology. 2008 Sep 23;71(13):997-9. doi: 10.1212/01.wnl.0000326592.37105.88.

PubMed [citation]

PMID:: 18809835

There is variability in the attainment of developmental milestones in the CDKL5 disorder.

Fehr S, Leonard H, Ho G, Williams S, de Klerk N, Forbes D, Christodoulou J, Downs J.

J Neurodev Disord. 2015;7(1):2. doi: 10.1186/1866-1955-7-2. Epub 2015 Jan 5.

PubMed [citation]

PMID:: 25657822
PMCID:: PMC4318547

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001374486.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CDKL5 protein function. ClinVar contains an entry for this variant (Variation ID: 11505). This missense change has been observed in individual(s) with clinical features of CDKL5-related disorder (PMID: 18809835, 25657822). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 291 of the CDKL5 protein (p.Cys291Tyr).

#	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

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