ClinVar Miner

Submissions for variant NM_003159.2(CDKL5):c.1234A>G (p.Lys412Glu) (rs770340766)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481169 SCV000573654 uncertain significance not provided 2017-02-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CDKL5 gene. The K412E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The K412E variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The K412E 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. In silico analysis is inconsistent in its predictions as to whether or not the variant is 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 RCV000686829 SCV000814365 uncertain significance Early infantile epileptic encephalopathy 2; Angelman syndrome-like 2018-05-02 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 412 of the CDKL5 protein (p.Lys412Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs770340766, ExAC 0.002%). This variant has not been reported in the literature in individuals with CDKL5-related disease. ClinVar contains an entry for this variant (Variation ID: 423898). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). 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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