ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.119C>T (p.Ala40Val) (rs122460159)

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Total submissions: 7
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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, ClinGen RCV001507073 SCV001712048 pathogenic CDKL5 disorder 2021-03-30 reviewed by expert panel curation The p.Ala40Val variant in CDKL5 has been reported in at least 4 unconfirmed de novo occurrences in patients with CDKL5 disorder (PMID 27779742, 17993579, 22678952, 19793311) (PM6_VS). It is also reported in the mosaic state in a male patient with CDKL5 disorder (PMID 25819767) and therefore confirmed to be de novo (PS2). The p.Ala40Val variant has been observed in at least 10 other individuals with CDKL5 disorder (27779742, 25819767, 17993579, 22678952, 19793311, 21309761, 19780792) (PS4). The variant is absent in gnomAD (PM2_supporting). The variant is located in a well-characterized (ATP binding region: aa 19-43) functional domain of CDKL5 (PMID: 28544139, 17993579, 23064044, 29264392) (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Ala40Val in CDKL5 is classified as Pathogenic based on the ACMG/AMP criteria (PM6_very strong, PS2, PS4_strong, PM1, PM2_supporting, PP3).
Invitae RCV000699210 SCV000827910 pathogenic Early infantile epileptic encephalopathy 2; Angelman syndrome-like 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 40 of the CDKL5 protein (p.Ala40Val). The alanine residue is moderately 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 individuals with CDKL5-related disorders (PMID: 17993579, 25819767, 22678952, 19780792). ClinVar contains an entry for this variant (Variation ID: 11502). Experimental studies have shown that this missense change causes mislocalization of the mutant protein to the nucleus (PMID: 17993579, 19793311). Variants that disrupt the p.Ala40 amino acid residue in CDKL5 have been observed in affected individuals (PMID: 27848944). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV000012257 SCV001164152 pathogenic Early infantile epileptic encephalopathy 2 2017-06-29 criteria provided, single submitter clinical testing
GeneDx RCV001564884 SCV001788124 pathogenic not provided 2019-10-02 criteria provided, single submitter clinical testing Published functional studies demonstrate that A40V results in the mislocalization of the CDKL5 protein (Rosas-Vargas et al., 2008); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; A different missense change at this residue (A40E) and nearby residues have been reported in the Human Gene Mutation Database (Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31302675, 30898514, 22678952, 19780792, 19793311, 27779742, 27848944, 25819767, 17993579)
OMIM RCV000012257 SCV000032491 pathogenic Early infantile epileptic encephalopathy 2 2009-10-01 no assertion criteria provided literature only
RettBASE RCV000133317 SCV000188326 pathogenic Atypical Rett syndrome 2014-03-13 no assertion criteria provided curation In vitro study shows mislocalisation of CDKL5 in the cytoplasm
RettBASE RCV000012257 SCV000222299 pathogenic Early infantile epileptic encephalopathy 2 2014-03-13 no assertion criteria provided curation In vitro study shows mislocalisation of CDKL5 in the cytoplasm

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