ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.743G>T (p.Arg248Leu) (rs1064795857)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484884 SCV000572058 uncertain significance not provided 2016-10-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CDKL5 gene. The R248L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R248L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001041210 SCV001204812 uncertain significance Early infantile epileptic encephalopathy 2; Angelman syndrome-like 2019-03-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 248 of the CDKL5 protein (p.Arg248Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDKL5-related conditions. ClinVar contains an entry for this variant (Variation ID: 422559). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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