Submissions for variant NM_001323289.2(CDKL5):c.456_457del (p.Cys152_Asp153delinsTer)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002472209	SCV002769294	pathogenic	Developmental and epileptic encephalopathy, 2	2020-05-21	criteria provided, single submitter	clinical testing	A heterozygous nonsense variant was identified, NM_003159.2(CDKL5):c.456_457delTG in exon 7 of 21 of the CDKL5 gene. This nonsense variant is predicted to create a change of a cysteine to a stop at amino acid position 152 of the protein; NP_003150.1(CDKL5):p.(Cys152*), resulting in the loss of normal protein function through nonsense-mediated decay (NMD). The variant is not present in the gnomAD population database. The variant has been previously reported in a patient with CDKL5 disorder (Fehr, S. et al. (2015), RettBase). Other variants predicted to cause NMD have also been reported as pathogenic in individuals with CDKL5 disorder (ClinVar). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Centre for Population Genomics, CPG	RCV004725300	SCV005335322	likely pathogenic	CDKL5 disorder	2024-07-17	criteria provided, single submitter	curation	This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as likely pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant is absent from gnomAD (PM2_Supporting).