ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.1684A>G (p.Thr562Ala)

gnomAD frequency: 0.00001  dbSNP: rs376341076
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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 RCV003159619 SCV003853570 likely benign CDKL5 disorder 2025-02-28 reviewed by expert panel curation The highest population minor allele frequency of the c.1684A>G (p.Thr562Ala) variant in CDKL5 in gnomAD v4.1 is 0.000004 in the European (Non-Finnish) population (not sufficient to meet BS1 criteria). The computational predictor REVEL gives a score of 0.133, evidence that does not predict a damaging effect on CDKL5 function (BP4). The p.Thr562Ala variant is observed in at least 2 unaffected individuals (Ambry Genetics: internal database, Labcorp Genetics Inc. (formerly Invitae): internal database) (BS2). In summary, the p.Thr562Ala variant in CDKL5 is classified as Likely Benign for CDKL5-associated disorder based on the ACMG/AMP criteria (BP4, BS2) (CDKL5 Specifications v.3.0; curation approved on 02/28/2025).
Genetic Services Laboratory, University of Chicago RCV000501261 SCV000593965 uncertain significance not specified 2016-08-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV002316434 SCV000850989 uncertain significance Inborn genetic diseases 2016-05-02 criteria provided, single submitter clinical testing The p.T562A variant (also known as c.1684A>G), located in coding exon 11 of the CDKL5 gene, results from an A to G substitution at nucleotide position 1684. The threonine at codon 562 is replaced by alanine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs376341076. Based on data from the NHLBI Exome Sequencing Project (ESP), the G allele was absent out of 2443 total male alleles studied. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV001034114 SCV001197439 likely benign Developmental and epileptic encephalopathy, 2; Angelman syndrome-like 2023-12-09 criteria provided, single submitter clinical testing
Centre for Population Genomics, CPG RCV003159619 SCV005335300 likely benign CDKL5 disorder 2024-07-12 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 benign. At least the following criteria are met: The variant is observed in at least 2 individuals with no features of CDKL5 disorder (BS2). ClinVar Variation ID: 434666 There are 4 individuals in gnomAD v4 (1 hemizygote), AF <0.008% Computational prediction analysis tools suggest no impact on gene product (REVEL score <= 0.15) (BP4).

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