ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.854G>A (p.Arg285Lys) (rs1064795672)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481012 SCV000571696 likely pathogenic not provided 2016-09-20 criteria provided, single submitter clinical testing A novel R285K variant that is likely pathogenic has been identified in the CDKL5 gene. The R285K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. A different missense substitution at the same position (R285S) has been reported in an individual with early-onset epileptic encephalopathy and developmental delay (Moseley et al., 2012). The R285K variant 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. 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. Furthermore, a missense variant in a nearby residue (T288I) has been reported in the Human Gene Mutation Database in association with a CDKL5-related disorder (Stenson et al., 2014). However, the R285K variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV001244046 SCV001417239 pathogenic Early infantile epileptic encephalopathy 2; Angelman syndrome-like 2019-11-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 285 of the CDKL5 protein (p.Arg285Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of CDKL5-related conditions (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 422272). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg285 amino acid residue in CDKL5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29264392, Invitae). 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.

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