NM_001323289.2(CDKL5):c.532C>T (p.Arg178Trp) AND multiple conditions

Clinical significance:Pathogenic (Last evaluated: May 16, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000544362.1

Allele description [Variation Report for NM_001323289.2(CDKL5):c.532C>T (p.Arg178Trp)]

NM_001323289.2(CDKL5):c.532C>T (p.Arg178Trp)

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.532C>T (p.Arg178Trp)
Other names:
p.R178W:CGG>TGG
HGVS:
  • NC_000023.11:g.18584331C>T
  • NG_008475.1:g.163727C>T
  • NM_001037343.2:c.532C>T
  • NM_001323289.2:c.532C>TMANE SELECT
  • NM_003159.2:c.532C>T
  • NM_003159.3:c.532C>T
  • NP_001032420.1:p.Arg178Trp
  • NP_001310218.1:p.Arg178Trp
  • NP_003150.1:p.Arg178Trp
  • NP_003150.1:p.Arg178Trp
  • NC_000023.10:g.18602451C>T
  • p.(Arg178Trp)
Protein change:
R178W
Links:
RettBASE (CDKL5): 69; dbSNP: rs267608493
NCBI 1000 Genomes Browser:
rs267608493
Molecular consequence:
  • NM_001037343.2:c.532C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001323289.2:c.532C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003159.2:c.532C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003159.3:c.532C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Early infantile epileptic encephalopathy 2 (DEE2)
Synonyms:
INFANTILE SPASM SYNDROME, X-LINKED 2
Identifiers:
MONDO: MONDO:0010396; MedGen: C4750718; Orphanet: 1934; Orphanet: 3451; OMIM: 300672
Name:
Angelman syndrome-like
Identifiers:
MedGen: CN128785

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000639479Invitaecriteria provided, single submitter
Pathogenic
(May 16, 2017)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000639479.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces arginine with tryptophan at codon 178 of the CDKL5 protein (p.Arg178Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with severe epileptic encephalopathy, infantile spasms and Rett syndrome like features (PMID: 19793311, 22678952, 19362436, 25657822, 22872100, 22430159). This variant has also been observed as a de novo event in an individual with early infantile epileptic encephalopathy(PMID: 26993267). ClinVar contains an entry for this variant (Variation ID: 143823). Different recurrent missense substitutions at this codon (p.Arg178Pro and p.Arg178Gln) have been determined to be pathogenic (PMID: 22678952, 19793311, 22670135, 26271793, 26482601). This suggests that the arginine residue is critical for CDKL5 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 20, 2021

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