NM_001323289.2(CDKL5):c.119C>T (p.Ala40Val) AND CDKL5 disorder

Clinical significance:Pathogenic (Last evaluated: Mar 30, 2021)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001507073.1

Allele description [Variation Report for NM_001323289.2(CDKL5):c.119C>T (p.Ala40Val)]

NM_001323289.2(CDKL5):c.119C>T (p.Ala40Val)

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.119C>T (p.Ala40Val)
HGVS:
  • NC_000023.11:g.18564496C>T
  • NG_008475.1:g.143892C>T
  • NM_001037343.1:c.119C>T
  • NM_001037343.2:c.119C>T
  • NM_001323289.2:c.119C>TMANE SELECT
  • NM_003159.2:c.119C>T
  • NM_003159.3:c.119C>T
  • NP_001032420.1:p.Ala40Val
  • NP_001032420.1:p.Ala40Val
  • NP_001310218.1:p.Ala40Val
  • NP_003150.1:p.Ala40Val
  • NP_003150.1:p.Ala40Val
  • NC_000023.10:g.18582616C>T
  • NM_003159.2(CDKL5):c.119C>T
  • O76039:p.Ala40Val
Protein change:
A40V; ALA40VAL
Links:
RettBASE (CDKL5): 44; UniProtKB: O76039#VAR_058022; OMIM: 300203.0009; dbSNP: rs122460159
NCBI 1000 Genomes Browser:
rs122460159
Molecular consequence:
  • NM_001037343.1:c.119C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001037343.2:c.119C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001323289.2:c.119C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003159.2:c.119C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003159.3:c.119C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001712048ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, ClinGenreviewed by expert panel
Pathogenic
(Mar 30, 2021)
germlinecuration

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, ClinGen, SCV001712048.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The p.Ala40Val variant in CDKL5 has been reported in at least 4 unconfirmed de novo occurrences in patients with CDKL5 disorder (PMID 27779742, 17993579, 22678952, 19793311) (PM6_VS). It is also reported in the mosaic state in a male patient with CDKL5 disorder (PMID 25819767) and therefore confirmed to be de novo (PS2). The p.Ala40Val variant has been observed in at least 10 other individuals with CDKL5 disorder (27779742, 25819767, 17993579, 22678952, 19793311, 21309761, 19780792) (PS4). The variant is absent in gnomAD (PM2_supporting). The variant is located in a well-characterized (ATP binding region: aa 19-43) functional domain of CDKL5 (PMID: 28544139, 17993579, 23064044, 29264392) (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Ala40Val in CDKL5 is classified as Pathogenic based on the ACMG/AMP criteria (PM6_very strong, PS2, PS4_strong, PM1, PM2_supporting, PP3).

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

Last Updated: Nov 20, 2021

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