ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.2555C>T (p.Pro852Leu)

gnomAD frequency: 0.00011  dbSNP: rs587783156
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Total submissions: 5
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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 RCV003235063 SCV003933681 benign CDKL5 disorder 2023-04-14 reviewed by expert panel curation The allele frequency of the p.Pro852Leu variant in CDKL5 is 0.031% in African sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Pro852Leu variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1).
GeneDx RCV000144835 SCV000191074 likely benign not provided 2020-04-10 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001053868 SCV001218151 likely benign Developmental and epileptic encephalopathy, 2; Angelman syndrome-like 2025-01-23 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV003338420 SCV004047103 uncertain significance Developmental and epileptic encephalopathy, 2 criteria provided, single submitter clinical testing The missense variant c.2555C>T (p.Pro852Leu) in CDKL5 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant has been reported to the ClinVar database with conflicting interpretations of pathogenicity as Likely Benign/Uncertain Significance. The p.Pro852Leu variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Pro at position 852 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT and the residue is conserved across species. The amino acid change p.Pro852Leu in CDKL5 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Ambry Genetics RCV004975294 SCV005559207 likely benign Inborn genetic diseases 2024-08-10 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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