ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000080074 SCV000190959 pathogenic not provided 2017-04-14 criteria provided, single submitter clinical testing The R178Q missense pathogenic variant in the CDKL5 gene has been reported multiple times previously as a de novo change in individuals with early onset epileptic encephalopathy (Liang et al., 2011; Bahi-Buisson et al., 2012; Carvill et al., 2013; Zhao et al., 2014; Kobayashi et al., 2016). The R178Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R178Q pathogenic variant is a semi-conservative amino acid substitution, which alters a conserved position predicted to be within the protein kinase domain. Missense variants at the same position (R178W/P) and in nearby residues (R175S, W176L, Y177C, P180L, L182P) have been reported in the Human Gene Mutation Database in association with CDKL5-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function.
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 2019-07-29 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)

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