Variant: NM_001323289.2(CDKL5):c.2684C>T (p.Pro895Leu)

CA294762

1701032 (ClinVar)

Gene: CDKL5

Condition: CDKL5 disorder

Inheritance Mode: X-linked inheritance

UUID: 54bdf8ff-1576-457e-873a-0646efcfcafe

Approved on: 2025-02-28

Published on: 2025-03-28

HGVS expressions

NM_001323289.2:c.2684C>T
NM_001323289.2(CDKL5):c.2684C>T (p.Pro895Leu)
NC_000023.11:g.18628558C>T
CM000685.2:g.18628558C>T
NC_000023.10:g.18646678C>T
CM000685.1:g.18646678C>T
NC_000023.9:g.18556599C>T
NG_008475.1:g.207954C>T
ENST00000623535.2:c.2684C>T
ENST00000674046.1:c.2807C>T
ENST00000379989.6:c.2684C>T
ENST00000379996.7:c.2684C>T
ENST00000623535.1:c.2684C>T
NM_001037343.1:c.2684C>T
NM_003159.2:c.2684C>T
NM_001323289.1:c.2684C>T
NM_001037343.2:c.2684C>T
NM_003159.3:c.2684C>T

Uncertain Significance

• Met criteria codes: PS2 BS1 BP4

• Not Met criteria codes: PS4 PP4 PP3 PM6 PM1

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 4.0.0

Evidence submitted by expert panel

Rett and Angelman-like Disorders VCEP

The highest population minor allele frequency of the c.2684C>T (p.Pro895Leu) variant in CDKL5 in gnomAD v4.1 is 0.0001 in the East Asian population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). This variant has been identified as a de novo occurrence in 1 individual mosaic for this variant (mosaicism confirmed, PMID: 37088138) (PS2). The p.Pro895Leu variant has been reported in 1 proband with a neurodevelopmental phenotype consistent with CDKL5 disorder. However, PS4 cannot be applied because PM2 does not apply (PS4_not met) and the described phenotype does not meet PP4 criteria (PMID: 27770071) (PP4_Not met). The computational predictor REVEL gives a score of 0.241, which is below the threshold of 0.290, evidence that does not predict a damaging effect on CDKL5 function (BP4). In summary, the p.Pro895Leu variant in CDKL5 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS1, PS2, BP4) (CDKL5 Specifications v4.0; curation approved on 02/28/2025).

Met criteria codes

• PS2: This variant has been identified as a de novo occurrence in 1 individual mosaic for this variant (mosaicism confirmed) (PMID: 37088138) (PS2).
• BS1: The highest population minor allele frequency of the p.Pro895Leu variant in CDKL5 in gnomAD v4.1 is 0.0001 in the East Asian population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1).
• BP4: The computational predictor REVEL gives a score of 0.241, which is below the threshold of 0.290, evidence that does not predict a damaging effect on CDKL5 function (BP4).

Not Met criteria codes

• PS4: The p.Pro895Leu variant has been reported in 1 proband with a neurodevelopmental phenotype consistent with CDKL5 disorder. However, PS4 cannot be applied because additional independent observations are needed (PS4_not met)
• PP4: The described phenotype does not meet PP4 criteria (PMID 27770071) (PP4_Not met).
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: This variant is outside ATP binding region: aa 19-43; TEY phosphorylation site: aa 169-171 (PM1 not met).