ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.2842C>T (p.Arg948Ter) (rs1555955296)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000578897 SCV000681295 uncertain significance not provided 2019-01-11 criteria provided, single submitter clinical testing The R948X variant, present in an alternate transcript of the CDKL5 gene, has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function through protein truncation. The R948X variant is not observed in large population cohorts (Lek et al., 2016). We interpret R948X as a variant of uncertain significance.
Undiagnosed Diseases Network,NIH RCV000735202 SCV000863408 pathogenic Early infantile 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 19, 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 19 in the same transcript NM_001323289.1 (PMID: 29444904).

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