Submissions for variant NM_001323289.2(CDKL5):c.528G>T (p.Trp176Cys)

dbSNP: rs786204989

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850413	SCV002242166	pathogenic	Developmental and epileptic encephalopathy, 2; Angelman syndrome-like	2022-08-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp176 amino acid residue in CDKL5. Other variant(s) that disrupt this residue have been observed in individuals with CDKL5-related conditions (PMID: 23064044), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CDKL5 protein function. ClinVar contains an entry for this variant (Variation ID: 189595). This missense change has been observed in individual(s) with clinical features of CDKL5-related conditions (DOI: 10.3233/PEP-2012-005). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 176 of the CDKL5 protein (p.Trp176Cys).
Centre for Population Genomics, CPG	RCV004725010	SCV005335255	pathogenic	CDKL5 disorder	2024-07-04	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 pathogenic. At least the following criteria are met: This variant is absent from gnomAD v4 (PM2_Supporting). At least one individual with this variant has been reported with a clinical phenotype consistent with CDKL5- related condition (PP4). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). Has been observed in at least 3 individuals with phenotypes consistent with CDKL5 disorder (PS4_Moderate). PMID: 37490689 PMID: 33436160 ClinVar Variation ID: 189595 This variant has been identified as a de novo occurrence in an individual with CDKL5 disorder without confirmation of paternity and maternity (PM6). PMID: 33436160 >=2 different missense variants in the same codon have been classified as pathogenic (PM5_Strong). Variation ID: 189594 PMID: 23064044 PMID: 29655203
RettBASE	RCV000170050	SCV000222358	pathogenic	Atypical Rett syndrome	2014-05-15	no assertion criteria provided	curation	De novo mutation near phosphorylation site; In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = benign (C0)