ClinVar Miner

Submissions for variant NM_020822.3(KCNT1):c.785G>A (p.Arg262Gln) (rs1554771469)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497817 SCV000589778 likely pathogenic not provided 2016-09-16 criteria provided, single submitter clinical testing The R262Q variant in the KCNT1 gene has been reported previously as a de novo variant in an individual with malignant migrating focal seizures of infancy (Moller et al., 2015). The R262Q variant was not observed in approximately 6500 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 R262Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties and occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The R262Q variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV001058624 SCV001223209 pathogenic Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2019-05-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 262 of the KCNT1 protein (p.Arg262Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been shown to arise de novo in individuals affected with malignant partial seizures of infancy (PMID: 26122718) as well as intractable focal epilepsy with pervasive developmental disorder (Invitae database). ClinVar contains an entry for this variant (Variation ID: 432096). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. For these reasons, this variant has been classified as Pathogenic.

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