ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.2842C>T (p.Arg948Ter)

dbSNP: rs1555955296
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Total submissions: 5
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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 RCV002281117 SCV002569929 pathogenic CDKL5 disorder 2022-09-01 reviewed by expert panel curation The p.Arg948Ter variant in CDKL5 is absent from gnomAD (PM2_Supporting). The p.Arg948Ter variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with features of CDKL5-associated disorder (PMID 32366967; internal database) (PS2_Very Strong). The p.Arg948Ter variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. While loss-of-function variants are commonly observed in affected individuals in this gene, there is a paucity of these variants in this region of the gene to date (PVS1). In summary, the p.Arg948Ter variant in CDKL5 is classified as pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PM2_Supporting, PS2_Very Strong, PVS1).
GeneDx RCV000578897 SCV000681295 pathogenic not provided 2021-06-25 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation as the last 13 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed at significant frequency in large population cohorts (Lek 2006).; This variant is associated with the following publications: (PMID: 31814998, 32366967, 27535533)
Undiagnosed Diseases Network, NIH RCV000735202 SCV000863408 pathogenic Developmental and epileptic encephalopathy, 2 2018-09-05 criteria provided, single submitter clinical testing This variant was reported by the clinical laboratory as pathogenic in July 2018. Previous testing at a different laboratory in October 2016 did not report the variant because it was only in a coding region on transcript NM_001323289.1 and not the other isoforms of CDKL5, including the canonical transcript. This transcript was added to NCBI RefSeq database in April 2016 but had not yet been curated into their annotation set and so was not included in their analysis in October 2016. This variant is present in the NM_001323289.1 transcript, which is confirmed to be expressed in the brain in both humans and mice. Our patient's variant is located in exon 17, which is longer in this alternative transcript than in the canonical transcript. Earlier this year, a male patient with intractable seizures was reported to have a de novo frameshift mutation within the same exon 17 in the same transcript NM_001323289.1 (PMID: 29444904).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002281117 SCV003922279 pathogenic CDKL5 disorder 2023-05-02 criteria provided, single submitter curation The hemizygous p.Arg948Ter variant in CDKL5 was identified by our study in one individual with infantile-onset epilepsy (Broad Institute Rrae Genomes Project). Trio genome analysis showed this variant to be de novo. The p.Arg948Ter variant in CDKL5 has been previously reported in two unrelated individuals with developmental and epileptic encephalopathy 2 (PMID: 32366967, ClinVar SCV002569929.1). This variant was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 489299) and has been interpreted as pathogenic by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, NIH Undiagnosed Diseases Network, and GeneDx. This nonsense variant leads to a premature termination codon at position 948. This alteration occurs within the terminal 50 bases of the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the CDKL5 gene is an established disease mechanism in X-linked developmental and epileptic encephalopathy 2. In summary, this variant meets criteria to be classified as pathogenic for developmental and epileptic encephalopathy 2. ACMG/AMP Criteria applied: PVS1_Strong, PS2, PM2_Supporting (Richards 2015).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017682 SCV004848397 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2020-07-08 criteria provided, single submitter clinical testing The p.Arg948X variant in CDKL5 has been reported in the hemizygous state in a young male with infantile spasms, atonic seizures, developmental delays, and regression (Schoch et al, 2020) and in the heterozygous state in a young female with infantile spasms, epilepsy, and developmental delay (Broad Institute Rare Genomes Project). In both individuals the variant was found to be de novo through trio whole genome sequence analysis. This variant has also been reported by a clinical laboratory in ClinVar (Variation ID 482247) and is absent from large population studies. This variant is present in the NM_001323289.2 transcript, which is confirmed to be expressed in the brain in both humans and mice (Hector RD et al 2016). This nonsense variant leads to a premature termination codon at position 948. This alteration occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. However, identification of other de novo truncating variants in this region suggest the region is critical for protein function. In summary, this variant meets criteria to be classified as pathogenic for X-linked dominant early infantile epileptic encephalopathy based on case observations, de novo occurrence, absence from large population studies, and predicted impact on protein. ACMG/AMP Criteria applied: PS2, PVS1_Strong, PM2_Supporting.

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