Submissions for variant NM_001323289.2(CDKL5):c.470C>T (p.Ala157Val)

dbSNP: rs863225066

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV003235124	SCV003933694	likely pathogenic	CDKL5 disorder	2023-04-14	reviewed by expert panel	curation	The p.Ala157Val variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with infantile epilepsy (GeneDx Internal Database) (PS2). The p.Ala157Val variant in CDKL5 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Ala157Val variant has been observed in individuals reported to have Rett syndrome or CDKL5 Deficiency disorder, however, additional clinical and segregation information was not provided (PMID: 32472944; 31313283) (PS4_supporting_met, PP4_not met). A pathogenic missense variant (p.Ala157Pro) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (Invitae internal database). In summary, the p.Ala157Val variant in CDKL5 is classified as likely pathogenic for CDKL5-related disorder based on the ACMG/AMP criteria (PS2, PP3, PM2_supporting, PS4_supporting,PM5).
CeGaT Center for Human Genetics Tuebingen	RCV000487793	SCV000575621	uncertain significance	not provided	2016-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000487793	SCV001769487	likely pathogenic	not provided	2021-03-31	criteria provided, single submitter	clinical testing	Reported in individuals in published literature with CDKL5-related disorders, but detailed clinical information and segregation information were not provided (Demarest et al., 2019; Cutri-French et al., 2020); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32472944, 31313283)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857739	SCV002132671	uncertain significance	Developmental and epileptic encephalopathy, 2; Angelman syndrome-like	2021-03-12	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces alanine with valine at codon 157 of the CDKL5 protein (p.Ala157Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with CDKL5-related conditions (PMID: 31313283). ClinVar contains an entry for this variant (Variation ID: 217360). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470811	SCV002768117	likely pathogenic	Developmental and epileptic encephalopathy, 2	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 2 (MIM#300672). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0601 - Variant is located within the well-established functional A-loop of the catalytic domain. Many pathogenic missense variants are located within this domain, which also displays a high intolerance to missense variation in gnomAD (NCBI, Decipher, PMID: 29264392). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported twice as a VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (LABID). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000201271	SCV000256047	uncertain significance	not specified	2015-02-13	no assertion criteria provided	clinical testing