ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.380A>G (p.His127Arg) (rs267608468)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000133366 SCV000190949 pathogenic not provided 2013-05-13 criteria provided, single submitter clinical testing The His127Arg substitution has been previously reported as a de novo mutation in a female with intractable epilepsy and severe intellectual disability (Russo et al., 2009). Although the amino acid substitution is conservative, it alters a highly conserved position in the Serine-Threonine kinase active site (Russo et al., 2009). The variant is found in EPILEPSY panel(s).
Invitae RCV001071921 SCV001237253 uncertain significance Early infantile epileptic encephalopathy 2; Angelman syndrome-like 2019-04-13 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 127 of the CDKL5 protein (p.His127Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with CDKL5-related conditions (PMID: 19241098). ClinVar contains an entry for this variant (Variation ID: 143818). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
RettBASE RCV000169914 SCV000188380 likely pathogenic Atypical Rett syndrome 2014-03-13 no assertion criteria provided curation In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = possibly pathogenic (C25)
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000133366 SCV000256049 pathogenic not provided 2015-02-13 no assertion criteria provided clinical testing

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