Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001323289.2(CDKL5):c.656A>C (p.Gln219Pro)

CA199370

189549 (ClinVar)

Gene: CDKL5 (HGNC:6792)

Condition: CDKL5 disorder (MONDO:0100039)

Inheritance Mode: X-linked inheritance

UUID: a1b11a90-1c4d-406b-85d8-9c6520d4df7c

Approved on: 2025-08-27

Published on: 2025-09-30

HGVS expressions

NM_001323289.2(CDKL5):c.656A>C (p.Gln219Pro)

NM_001323289.2:c.656A>C

NC_000023.11:g.18588055A>C

CM000685.2:g.18588055A>C

NC_000023.10:g.18606175A>C

CM000685.1:g.18606175A>C

NC_000023.9:g.18516096A>C

NG_008475.1:g.167451A>C

ENST00000623535.2:c.656A>C

ENST00000635828.1:c.656A>C

ENST00000637881.1:c.656A>C

ENST00000674046.1:c.656A>C

ENST00000379989.6:c.656A>C

ENST00000379996.7:c.656A>C

ENST00000463994.4:c.656A>C

ENST00000623535.1:c.656A>C

ENST00000623610.1:n.370A>C

NM_001037343.1:c.656A>C

NM_003159.2:c.656A>C

NM_001323289.1:c.656A>C

NM_001037343.2:c.656A>C

NM_003159.3:c.656A>C

Likely Pathogenic

PS4_Supporting PS2 PP3 PP4 PM2_Supporting PS3_Supporting

PS1 PM1 PM5

Evidence Links 0

Expert Panel

Rett and Angelman-like Disorders VCEP

Criteria Specification Information

Criteria Specification: ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDKL5 Version 5.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Rett and Angelman-like Disorders VCEP

The p.Gln219Pro variant has been observed in at least 2 individuals with CDKL5 disorder (PMID 23151060, internal database - Ambry) (PS4_Supporting). The p.Gln219Pro variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with CDKL5 disorder (internal database - Ambry) (PS2). The p.Gln219Pro variant in CDKL5 is present in an individual with a clinical phenotype suggestive of CDKL5 disorder (internal database - Ambry) (PP4). The p.Gln219Pro variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). In vitro kinase assay has shown that this variant impacts protein function (PMID: 32034940) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Gln219Pro variant in CDKL5 is classified as likely pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PS4_Supporting, PS2, PP4, PM2_Supporting, PS3_Supporting, PP3). (CDKL5 Specifications v.5.0.0; curation approved on 8/27/2025)

PS4_Supporting

The p.Gln219Pro variant has been observed in at least 2 individuals with CDKL5 disorder (PMID 23151060, internal database - Ambry).

PS2

The p.Gln219Pro variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with CDKL5 disorder (internal database - Ambry).

PP3

Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3).

PP4

The p.Gln219Pro variant in CDKL5 is present in an individual with a clinical phenotype suggestive of CDKL5 disorder (internal database - Ambry).

PM2_Supporting

The p.Gln219Pro variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting).

PS3_Supporting

In vitro kinase assay has shown that this variant impacts protein function (PMID 32034940).

PS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM5

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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