Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_001323289.2(CDKL5):c.470C>T (p.Ala157Val)

CA279171

217360 (ClinVar)

Gene: CDKL5
Condition: CDKL5 disorder
Inheritance Mode: X-linked inheritance
Link to MONDO
UUID: c746091d-5bd3-4f1a-a94c-7ce585edbb14
Approved on: 2023-04-14
Published on: 2023-06-16

HGVS expressions

NM_001323289.2:c.470C>T
NM_001323289.2(CDKL5):c.470C>T (p.Ala157Val)
NC_000023.11:g.18584269C>T
CM000685.2:g.18584269C>T
NC_000023.10:g.18602389C>T
CM000685.1:g.18602389C>T
NC_000023.9:g.18512310C>T
NG_008475.1:g.163665C>T
ENST00000623535.2:c.470C>T
ENST00000635828.1:c.470C>T
ENST00000637881.1:c.470C>T
ENST00000674046.1:c.470C>T
ENST00000379989.6:c.470C>T
ENST00000379996.7:c.470C>T
ENST00000463994.4:c.470C>T
ENST00000623535.1:n.470C>T
NM_001037343.1:c.470C>T
NM_003159.2:c.470C>T
NM_001323289.1:c.470C>T
NM_001037343.2:c.470C>T
NM_003159.3:c.470C>T
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Likely Pathogenic

Met criteria codes 5
PS4_Supporting PS2 PM2_Supporting PP3 PM5
Not Met criteria codes 1
PP4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Rett and Angelman-like Disorders VCEP
The p.Ala157Val variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with infantile epilepsy (GeneDx Internal Database) (PS2). The p.Ala157Val variant in CDKL5 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Ala157Val variant has been observed in individuals reported to have Rett syndrome or CDKL5 Deficiency disorder, however, additional clinical and segregation information was not provided (PMID: 32472944; 31313283) (PS4_supporting_met, PP4_not met). A pathogenic missense variant (p.Ala157Pro) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (Invitae internal database). In summary, the p.Ala157Val variant in CDKL5 is classified as likely pathogenic for CDKL5-related disorder based on the ACMG/AMP criteria (PS2, PP3, PM2_supporting, PS4_supporting,PM5).
Met criteria codes
PS4_Supporting
The p.Ala157Val variant has been observed in at least 2 individuals with neurological disease (PMID 32472944; 31313283)
PS2
The p.Ala157Val variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual (GeneDx Internal Database)
PM2_Supporting
The p.Ala157Val variant in CDKL5 is absent from gnomAD
PP3
Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own
PM5
A pathogenic missense variant (p.Ala157Pro) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (Invitae internal database)
Not Met criteria codes
PP4
Observed in individuals reported to have Rett syndrome or CDKL5 Deficiency disorder, however, additional clinical and segregation information was not provided (PMID: 32472944; 31313283)
Curation History
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