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]

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Variant: NM_001323289.2(CDKL5):c.2842C>T (p.Arg948Ter)

CA412369187

489299 (ClinVar)

Gene: CDKL5

Condition: CDKL5 disorder

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 6f4ef230-8fe8-4a41-9161-47767f6eabf7

Approved on: 2022-09-01

Published on: 2022-09-06

HGVS expressions

NM_001323289.2:c.2842C>T

NM_001323289.2(CDKL5):c.2842C>T (p.Arg948Ter)

NC_000023.11:g.18628716C>T

CM000685.2:g.18628716C>T

NC_000023.10:g.18646836C>T

CM000685.1:g.18646836C>T

NC_000023.9:g.18556757C>T

NG_008475.1:g.208112C>T

ENST00000623535.2:c.2842C>T

ENST00000674046.1:c.2965C>T

ENST00000379989.6:c.2713+129C>T

ENST00000379996.7:c.2713+129C>T

ENST00000623535.1:n.2842C>T

NM_001037343.1:c.2713+129C>T

NM_003159.2:c.2713+129C>T

NM_001323289.1:c.2842C>T

NM_001037343.2:c.2713+129C>T

NM_003159.3:c.2713+129C>T

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PVS1 PS2_Very Strong PM2_Supporting

Evidence Links 0

Expert Panel

Rett and Angelman-like Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Rett and Angelman-like Disorders VCEP

The p.Arg948Ter variant in CDKL5 is absent from gnomAD (PM2_Supporting). The p.Arg948Ter variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with features of CDKL5-associated disorder (PMID 32366967; internal database) (PS2_Very Strong). The p.Arg948Ter variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. While loss-of-function variants are commonly observed in affected individuals in this gene, there is a paucity of these variants in this region of the gene to date (PVS1). In summary, the p.Arg948Ter variant in CDKL5 is classified as pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PM2_Supporting, PS2_Very Strong, PVS1).

PVS1

The p.Arg948Ter variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. While loss-of-function variants are commonly observed in affected individuals in this gene, there is a paucity of these variants in this region of the gene to date (PVS1)

PS2_Very Strong

The p.Arg948Ter variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with features of CDKL5-associated disorder (PMID 32366967; internal database)

PM2_Supporting

The p.Arg948Ter variant in CDKL5 is absent from gnomAD

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