ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.1234A>G (p.Lys412Glu)

gnomAD frequency: 0.00001  dbSNP: rs770340766
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Total submissions: 3
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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 RCV001507072 SCV001712045 likely benign CDKL5 disorder 2023-08-28 reviewed by expert panel curation The p.Lys412Glu variant in CDKL5 is present in 1 XY individual in gnomAD (0.0001707%) (not sufficient to meet BS1 criteria). The p.Lys412Glu variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). Computational analysis prediction tools suggests that the p.Lys412Glu variant does not have a deleterious impact (BP4); however this information does not predict clinical significance on its own. In summary, the p.Lys412Glu variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4).
GeneDx RCV000481169 SCV000573654 likely benign not provided 2022-04-11 criteria provided, single submitter clinical testing See Variant Classification Assertion Criteria.
Invitae RCV000686829 SCV000814365 uncertain significance Developmental and epileptic encephalopathy, 2; Angelman syndrome-like 2023-01-07 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 423898). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CDKL5 protein function. This variant has not been reported in the literature in individuals affected with CDKL5-related conditions. This variant is present in population databases (rs770340766, gnomAD 0.001%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 412 of the CDKL5 protein (p.Lys412Glu). 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.

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