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.176G>A (p.Arg59Gln)

CA412348584

496681 (ClinVar)

Gene: CDKL5 (HGNC:6792)

Condition: CDKL5 disorder (MONDO:0100039)

Inheritance Mode: X-linked inheritance

UUID: 8d74cb24-aa24-4e8e-a22d-3a88b2c4fc39

Approved on: 2025-08-27

Published on: 2025-09-30

HGVS expressions

NM_001323289.2:c.176G>A

NM_001323289.2(CDKL5):c.176G>A (p.Arg59Gln)

NC_000023.11:g.18575384G>A

CM000685.2:g.18575384G>A

NC_000023.10:g.18593504G>A

CM000685.1:g.18593504G>A

NC_000023.9:g.18503425G>A

NG_008475.1:g.154780G>A

ENST00000623535.2:c.176G>A

ENST00000635828.1:c.176G>A

ENST00000637881.1:c.176G>A

ENST00000674046.1:c.176G>A

ENST00000379989.6:c.176G>A

ENST00000379996.7:c.176G>A

ENST00000463994.4:c.176G>A

ENST00000623364.3:c.176G>A

ENST00000623535.1:c.176G>A

ENST00000624700.3:c.176G>A

NM_001037343.1:c.176G>A

NM_003159.2:c.176G>A

NM_001323289.1:c.176G>A

NM_001037343.2:c.176G>A

NM_003159.3:c.176G>A

Uncertain Significance

PM6 BS2_Supporting

PM2 PM5 PM1 BS1 BP4 BA1 PP3

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 highest population minor allele frequency of the p.Arg59Gln variant in CDKL5 in gnomAD v4.1 is 0.00000112 in Non-Finnish European population (not sufficient to meet BS1 criteria). The p.Arg59Gln variant is observed in at least 1 unaffected individual (internal database - GeneDx) (BS2-supporting). Computational prediction analysis tools are inconclusive for this variant. The p.Arg59Gln variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with epileptic encephalopathy (internal database - Équipe Génétique des Anomalies du Développement (GAD)) (PM6). In summary, the p.Arg59Gln variant in CDKL5 is classified as uncertain significance based on the ACMG/AMP criteria (BS2_Supporting, PM6). (CDKL5 Specifications v.5.0.0; curation approved on 8/27/2025)

PM6

The p.Arg59Gln variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with epileptic encephalopathy (internal database - Équipe Génétique des Anomalies du Développement (GAD)).

BS2_Supporting

The p.Arg59Gln variant is observed in at least 1 unaffected individual (internal database - GeneDx).

PM2

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

PM1

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

BS1

The highest population minor allele frequency of the p.Arg59Gln variant in CDKL5 in gnomAD v4.1 is 0.00000112 in Non-Finnish European population (not sufficient to meet BS1 criteria).

BP4

Computational prediction analysis tools are inconclusive for this variant.

BA1

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

PP3

Computational prediction analysis tools are inconclusive for this variant.

Curation History

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