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]

Variant: NM_003159.2(CDKL5):c.2908C>T (p.Arg970Ter)

CA170485

143812 (ClinVar)

Gene: CDKL5
Condition: CDKL5 disorder
Inheritance Mode: X-linked inheritance
Link to MONDO
UUID: d1466290-ae92-4343-88ba-88e98b897c23
Approved on: 2023-12-06
Published on: 2023-12-08

HGVS expressions

NM_003159.2:c.2908C>T
NM_003159.2(CDKL5):c.2908C>T (p.Arg970Ter)
NC_000023.11:g.18650520C>T
CM000685.2:g.18650520C>T
NC_000023.10:g.18668640C>T
CM000685.1:g.18668640C>T
NC_000023.9:g.18578561C>T
NG_008475.1:g.229916C>T
NG_008659.3:g.31929G>A
ENST00000379984.4:c.185-3188G>A
ENST00000673617.1:n.180C>T
ENST00000379984.3:c.185-3188G>A
ENST00000379989.6:c.2908C>T
ENST00000379996.7:c.2908C>T
ENST00000476595.1:n.18G>A
NM_000330.3:c.185-3188G>A
NM_001037343.1:c.2908C>T
NM_000330.4:c.185-3188G>A
NM_001037343.2:c.2908C>T
NM_003159.3:c.2908C>T
NM_000330.4(RS1):c.185-3188G>A
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Benign

Met criteria codes 2
BS2 BS1
Not Met criteria codes 2
PP4 PM2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDKL5 Version 3.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Rett and Angelman-like Disorders VCEP
RS1(NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The allele frequency of the c.2908C>T (p.Arg970Ter) variant in CDKL5 transcript (NM_003159.2) is 0.02285% in the Middle Eastern sub population in gnomAD v4, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Arg970Ter variant in CDKL5 has been reported in an individual with a clinical phenotype suggestive of CDKL5 disorder (PMID 19428276), however this criterion cannot be applied due the allele frequency of the variant in gnomAD (PP4 not met). The p.Arg970Ter is observed in at least 5 unaffected individuals (internal database - GeneDx). In summary, the p.Arg970Ter variant in CDKL5 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2).
Met criteria codes
BS2
The p.Arg970Ter variant in CDKL5 (NM_001323289.2) is observed in at least 5 unaffected individuals (internal database - GeneDx).
BS1
The allele frequency of the c.2908C>T (p.Arg970Ter) variant in CDKL5 transcript (NM_003159.2) is 0.02285% in the Middle Eastern sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions.
Not Met criteria codes
PP4
A patient with this variant is reported to have a clinical phenotype suggestive of atypical Rett Syndrome PMID:19428276) (PP4)
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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