ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.533G>A (p.Arg178Gln) (rs267606715)

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Total submissions: 8
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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 RCV001507061 SCV001712029 pathogenic CDKL5 disorder 2021-03-25 reviewed by expert panel curation The p.Arg178Gln variant in CDKL5 has been reported in at least 4 de novo occurrences (biological parentage unconfirmed) in patients with CDKL5 disorder (PMID 26482601, 21770923, 29852413, 29190809, 24564546, 26482601) (PM6_very strong). The variant was present in the mosaic state in one patient, confirming its de novo nature (PMID 26482601) (PS2). The p.Arg178Gln variant in CDKL5 has been reported in at least 7 other individuals with CDKL5 disorder (PMID 26482601, 21770923, 29852413, 29190809, 24564546) (PS4). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 29100083, 22430159, 19793311, 18809835, 30182498) (PM5_strong). The p.Arg178Gln variant in CDKL5 is absent from gnomAD (PM2_supporting). In summary, the p.Arg178Gln variant in CDKL5 is classified as Pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PM6_very strong, PS2, PS4, PM5_strong, PM2_supporting).
GeneDx RCV000080074 SCV000190959 pathogenic not provided 2019-04-16 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21770923, 29190809, 31313283, 24564546, 23708187, 26482601, 22678952, 29852413, 32371413)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000080074 SCV000232632 likely pathogenic not provided 2013-04-02 criteria provided, single submitter clinical testing
Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospital RCV000169920 SCV001161762 pathogenic Early infantile epileptic encephalopathy 2 2017-12-08 criteria provided, single submitter clinical testing [ACMG/AMP: PS2, PM1, PM2, PM5, PS4_moderate, PP5]; A de novo mosaic variant [PS2] within the CDKL5 gene was detected and confirmed by sanger sequencing. This variant results in the replacement of an arginine by a glutamine at amino acid 178. The p.Arg178Gln variant has been previously documented in multiple individuals in the setting of early onset epileptic encephalopathy, with codon 178 described as a hotspot for disease-associated variation [PS4_moderate, PM5] (PMID: 21770923; 22678952; 24564546). This variant occurs within the kinase domain of the protein, specifically within subdomain VIII, a region important for substrate recognition [PM1] (PMID: 22678952). Functional studies of constructs with disease-associated variation demonstrate loss of kinase activity (PMID: 16330482). Kinome profiling in a CDKL5 deficient mouse model has demonstrated disruption of multiple signaling pathways suggestive of aberrant signal transduction in the setting of dysfunctional CDKL5 (PMID: 23236174). The p.Arg178Gln variant is absent from large-scale population databases including gnomAD [PM2], impacts a highly conserved nucleotide position, and has previously been reported as pathogenic [PP5] (ClinVar: 94113). Mosaicism in the setting of CDKL5-associated epileptic encephalopathy has been previously described in the literature, which further supports this mechanism in the pathogenesis of disease (PMID: 28837158; 20602487, 22779007).
Invitae RCV001201864 SCV001372955 pathogenic Early infantile epileptic encephalopathy 2; Angelman syndrome-like 2020-01-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 178 of the CDKL5 protein (p.Arg178Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with CDKL5-related conditions (PMID: 21770923, 24564546, 26482601, 29190809). ClinVar contains an entry for this variant (Variation ID: 94113). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). This variant disrupts the p.Arg178 amino acid residue in CDKL5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19793311, 22678952, 19362436, 25657822). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
RettBASE RCV000169920 SCV000188388 pathogenic Early infantile epileptic encephalopathy 2 2014-03-13 no assertion criteria provided curation Conserved residue, other missense at same position suspected pathogenic; In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = benign (C0)
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000080074 SCV001930285 likely pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000080074 SCV001955016 pathogenic not provided no assertion criteria provided clinical testing

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