ClinVar Genomic variation as it relates to human health

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).

For these reasons, this variant has been classified as Pathogenic. 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: 19362436, 19793311, 22678952, 25657822). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt CDKL5 protein function. ClinVar contains an entry for this variant (Variation ID: 94113). This missense change has been observed in individual(s) with CDKL5-related conditions (PMID: 21770923, 24564546, 26482601, 29190809). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 178 of the CDKL5 protein (p.Arg178Gln).

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: This variant has been identified as a de novo occurrence in an individual with CDKL5 disorder with confirmed parental relationships (PS2) PMID 26482601 Has been observed in at least 5 individuals with phenotypes consistent with CDKL5 disorder (PS4). PMID 26482601, 21770923, 29852413, 29190809, 24564546, Variation ID: 94113 This variant has been identified as a de novo occurrence in>=4 individuals with CDKL5 disorder syndrome without confirmation of paternity and maternity (PM6_very strong). PMID 26482601, 21770923, 29852413, 29190809, 24564546, 26482601 This variant is absent from gnomAD (PM2_Supporting).

[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).

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21770923, 29190809, 32371413, 33436160, 31313283, 24564546, 23708187, 26482601, 22678952, 29852413, 33047306)

Conserved residue, other missense at same position suspected pathogenic; In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = benign (C0)