NM_001323289.2(CDKL5):c.1892T>C (p.Ile631Thr) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 19, 2023
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:: RCV000700107.10

Allele description [Variation Report for NM_001323289.2(CDKL5):c.1892T>C (p.Ile631Thr)]

NM_001323289.2(CDKL5):c.1892T>C (p.Ile631Thr)

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.1892T>C (p.Ile631Thr)

Other names:

NM_001323289.2(CDKL5):c.1892T>C; p.Ile631Thr

HGVS:

NC_000023.11:g.18604816T>C
NG_008475.1:g.184212T>C
NM_001037343.2:c.1892T>C
NM_001323289.2:c.1892T>CMANE SELECT
NM_003159.3:c.1892T>C
NP_001032420.1:p.Ile631Thr
NP_001310218.1:p.Ile631Thr
NP_003150.1:p.Ile631Thr
NP_003150.1:p.Ile631Thr
NC_000023.10:g.18622936T>C
NM_003159.2:c.1892T>C

Protein change:

I631T

Links:

RettBASE (CDKL5): 71; dbSNP: rs144878564

NCBI 1000 Genomes Browser:

rs144878564

Molecular consequence:

NM_001037343.2:c.1892T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001323289.2:c.1892T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_003159.3:c.1892T>C - 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

Recent activity

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GDP-mannose transporter GONST1 isoform X1 [Cucumis sativus]
GDP-mannose transporter GONST1 isoform X1 [Cucumis sativus]
gi|778670215|ref|XP_011649404.1|

Protein
hypothetical protein SDJN03_01968, partial [Cucurbita argyrosperma subsp. sorori...
hypothetical protein SDJN03_01968, partial [Cucurbita argyrosperma subsp. sororia]
gi|2047938743|gb|KAG6608626.1||gnl| AGKQH|SDJN03_01968

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000828848	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 19, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19793311, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000828848

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 19, 2023)

germline

clinical testing

PubMed (2)
[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

Mutational spectrum of CDKL5 in early-onset encephalopathies: a study of a large collection of French patients and review of the literature.

Nemos C, Lambert L, Giuliano F, Doray B, Roubertie A, Goldenberg A, Delobel B, Layet V, N'guyen MA, Saunier A, Verneau F, Jonveaux P, Philippe C.

Clin Genet. 2009 Oct;76(4):357-71. doi: 10.1111/j.1399-0004.2009.01194.x. Review.

PubMed [citation]

PMID:: 19793311

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000828848.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 631 of the CDKL5 protein (p.Ile631Thr). This variant is present in population databases (rs144878564, gnomAD 0.02%). This missense change has been observed in individual(s) with seizures (PMID: 19793311). ClinVar contains an entry for this variant (Variation ID: 143786). 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 not expected to disrupt CDKL5 protein function with a negative predictive value of 95%. 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.

#	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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