ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.1196A>C (p.Asn399Thr) (rs267608611)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, ClinGen RCV001507054 SCV001712016 likely benign CDKL5 disorder 2021-04-02 reviewed by expert panel curation The p.Asn399Thr variant in CDKL5 is observed in at least 2 unaffected individuals (internal database) (BS2). This variant is also present in the heterozygous state in two individuals in gnomAD. Computational analysis prediction tools suggest that the p.Asn399Thr variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Asn399Thr variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4).
GeneDx RCV000479280 SCV000568364 uncertain significance not provided 2016-01-07 criteria provided, single submitter clinical testing The N399T variant in the CDKL5 gene has been reported previously in a female with Rett syndrome, whose mother did not carry the variant and her father was unavailable for testing (Sprovieri et al., 2009). The N399T 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 N399T variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Asparagine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret N399T as a variant of uncertain significance
Fulgent Genetics,Fulgent Genetics RCV000764869 SCV000896025 uncertain significance Early infantile epileptic encephalopathy 2 2018-10-31 criteria provided, single submitter clinical testing
RettBASE RCV000133316 SCV000188325 uncertain significance Atypical Rett syndrome 2014-03-13 no assertion criteria provided curation In silico predictions: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = benign, AlignGVGD = benign (C0)

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