rs267606715
Variant summary
Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS2PM2_SupportingPS4PM5_Strong
This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA199289/MONDO:0100039/016
Frequency
Consequence
NM_001323289.2 missense
Scores
Clinical Significance
Conservation
Publications
- CDKL5 disorderInheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
- developmental and epileptic encephalopathy, 2Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
- atypical Rett syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- genetic developmental and epileptic encephalopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- infantile spasmsInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- precocious pubertyInheritance: XL Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 13 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CDKL5 | NM_001323289.2 | c.533G>A | p.Arg178Gln | missense_variant | Exon 8 of 18 | ENST00000623535.2 | NP_001310218.1 | |
| CDKL5 | NM_001037343.2 | c.533G>A | p.Arg178Gln | missense_variant | Exon 9 of 22 | NP_001032420.1 | ||
| CDKL5 | NM_003159.3 | c.533G>A | p.Arg178Gln | missense_variant | Exon 8 of 21 | NP_003150.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1078524Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0AN XY: 345184
GnomAD4 genome
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 2 Pathogenic:7
The variant NM_001323289.2:c.533G>A (p.Arg178Gln) results in an arginine-to-glutamine substitution at codon 178. According to ACMG/AMP guidelines, this variant meets the criteria for PS4, PS2, PM5, PM2, PM1, PP3, and PP5, supporting its classification as pathogenic -
Conserved residue, other missense at same position suspected pathogenic; In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = benign (C0) -
The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.75 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.98 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000094113 /PMID: 21770923 /3billion dataset). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 21770923, 26482601, 27081548). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 21770923, 24564546, 26482601, 29190809, 29852413). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 21770923, 24564546, 26482601, 29190809, 29852413). Different missense changes at the same codon (p.Arg178Gly, p.Arg178Leu, p.Arg178Pro, p.Arg178Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000018450, VCV000143823, VCV001071237, VCV002159555 /PMID: 18809835, 19793311, 30182498). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
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[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). -
The observed missense variant c.533G>A(p.Arg178Gln) in CDKL5 gene has been reported previously in multiple individual(s) with CDKL5-related conditions. This variant disrupts the p.Arg178 amino acid residue in CDKL5. Other variant(s) that disrupt this residue have been determined to be pathogenic (MacKay CI, et al., 2021; Ortega-Moreno L, et al., 2017; Fehr S, et al., 2015; Bahi-Buisson N, et al., 2012). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant is absent in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic by mulitple submitters and is also reviewed as pathogenic by expert panel (FDA recognized database). The amino acid Arg at position 178 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Possibly damaging, SIFT – Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:4
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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) -
CDKL5 disorder Pathogenic:2
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). -
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). -
West syndrome Pathogenic:1
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Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Pathogenic:1
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 is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 94113). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CDKL5 protein function with a positive predictive value of 80%. 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. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at