ClinVar Miner

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

dbSNP: rs863225066
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Total submissions: 6
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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)
Invitae 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. 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. This variant has been observed in individual(s) with CDKL5-related conditions (PMID: 31313283). ClinVar contains an entry for this variant (Variation ID: 217360). This variant is not present in population databases (ExAC no frequency). 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.
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

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