ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.524G>T (p.Arg175Ile) (rs1064794734)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478501 SCV000569835 likely pathogenic not provided 2016-03-29 criteria provided, single submitter clinical testing The R175I variant in the CDKL5 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R175I 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. The R175I 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (R175S) as well as nearby residues (Y171D, W176L, R178W, R178Q, R178P, P180L) have been reported in the Human Gene Mutation Database in association with CDKL5-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available information, R175I is a strong candidate for a pathogenic variant, however, the possibility it may be a rare benign variant cannot be excluded.

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