Submissions for variant NM_001323289.2(CDKL5):c.533G>C (p.Arg178Pro)

dbSNP: rs267606715

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001035195	SCV001198510	pathogenic	Developmental and epileptic encephalopathy, 2; Angelman syndrome-like	2021-10-27	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects CDKL5 function (PMID: 19793311). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg178 amino acid residue in CDKL5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19362436, 19793311, 22678952, 25657822, 26482601, 29190809). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 18450). This missense change has been observed in individual(s) with clinical features of CDKL5-related condition (PMID: 18809835, 19793311, 30776697). 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 arginine, a(n) basic and polar amino acid, with proline, a(n) neutral and non-polar amino acid, at codon 178 of the CDKL5 protein (p.Arg178Pro).
Centre for Population Genomics, CPG	RCV004724751	SCV005335247	likely pathogenic	CDKL5 disorder	2024-09-23	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: This variant has been identified as a de novo occurrence in at least 2 individuals with CDKL5 disorder, without confirmation of paternity and maternity (PM6_Strong, PMID: 19793311, PMID: 22678952, PMID: 21770923). Has been observed in at least 3 individuals with phenotypes consistent with CDKL5 disorder (PS4_Moderate, PMIDs: 21770923, 22678952, 19793311, 18809835). This variant is absent from gnomAD (PM2_Supporting).
OMIM	RCV000012262	SCV000032496	pathogenic	Developmental and epileptic encephalopathy, 2	2009-10-01	no assertion criteria provided	literature only
RettBASE	RCV000012262	SCV000188389	pathogenic	Developmental and epileptic encephalopathy, 2	2014-03-13	no assertion criteria provided	curation	Highly conserved residue, one male patient (healthy mother not carrier), de novo in second patient (female); In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = benign (C0)