ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.215T>C (p.Ile72Thr) (rs62641235)

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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, ClinGen RCV001507029 SCV001711973 pathogenic CDKL5 disorder 2021-03-26 reviewed by expert panel curation The p.Ile72Thr variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with CDKL5 disease (PMID 19396824, 19241098) (PM6). The p.Ile72Thr variant in CDKL5 has been reported in at least 3 other individuals with CDKL5 disease (PMID 19396824, 19241098, 25657822, ClinVar) (PS4_moderate). The p.Ile72Thr variant in CDKL5 is absent from gnomAD (PM2). Multiple likely pathogenic missense variants have been previously identified within this codon (p.Ile72Asn; p.Ile72Met) which indicates that this residue is critical to the function of the protein (PMID 28074849, 27779742, 16015284) (PM5_strong). Phosphoproteomic screening of the cellular substrates of CDKL5 (MAP1S, CEP131 and DLG5) has shown that the p.Ile72Thr variant impacts protein function (PMID 30266825) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own(PP3). In summary, the p.Ile72Thr variant in CDKL5 is classified as Pathogenic for CDKL5 disease based on the ACMG/AMP criteria (PM5_strong, PM6, PS4_moderate, PS3_supporting, PM2_supporting, PP3).
GeneDx RCV000080068 SCV000190942 pathogenic not provided 2019-07-30 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19396824, 19241098, 25657822, 29655203, 22779007, 22670135, 31313283, 31302675)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000080068 SCV000231043 pathogenic not provided 2015-03-10 criteria provided, single submitter clinical testing
Invitae RCV001385703 SCV001585663 pathogenic Early infantile epileptic encephalopathy 2; Angelman syndrome-like 2020-01-08 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 72 of the CDKL5 protein (p.Ile72Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with early infantile epileptic encephalopathy/West syndrome (PMID: 19396824). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11503). This variant has been reported to affect CDKL5 protein function (PMID: 30266825). This variant disrupts the p.Ile72 amino acid residue in CDKL5. Other variant(s) that disrupt this residue have been observed in individuals with CDKL5-related conditions (PMID: 28074849, 27779742, 16015284), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000012258 SCV000032492 pathogenic Early infantile epileptic encephalopathy 2 2009-05-01 no assertion criteria provided literature only
RettBASE RCV000169913 SCV000188354 pathogenic Rett syndrome 2016-04-26 no assertion criteria provided research

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