ClinVar Miner

Submissions for variant NM_020822.3(KCNT1):c.1283G>A (p.Arg428Gln) (rs397515402)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000413614 SCV000854874 pathogenic not provided 2017-10-30 criteria provided, single submitter clinical testing
GeneDx RCV000413614 SCV000490583 pathogenic not provided 2018-05-21 criteria provided, single submitter clinical testing The R428Q variant in the KCNT1 gene has been reported previously as pathogenic variant occurring in multiple unrelated individuals with MMPSI (Barcia et al., 2012; Bearden et al., 2014). Functional characterization of the R428Q variant indicates a strong gain-of-function in KCNT1 channel properties, which correlate with the more severe MMPSI phenotype (Milligan et al., 2014). It is reported as pathogenic in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000151541.1; Landrum et al., 2016). The R428Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R428Q variant is a semi-conservative amino acid substitution of a residue that is well-conserved across species. We interpret R428Q as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000117358 SCV000151541 pathogenic Epilepsy, nocturnal frontal lobe, 5 2013-12-12 criteria provided, single submitter clinical testing
Invitae RCV000805871 SCV000945845 pathogenic Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 428 of the KCNT1 protein (p.Arg428Gln). The arginine residue is highly 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 observed to be de novo in individuals with early infantile epileptic encephalopathy (PMID: 23086397, 26140313). ClinVar contains an entry for this variant (Variation ID: 39593). Experimental studies have shown that this missense change leads to an increase in current amplitude and causes constitutive activation of the potassium channel (PMID: 23086397, 24591078). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000032793 SCV000056561 pathogenic Early infantile epileptic encephalopathy 14 2012-11-01 no assertion criteria provided literature only

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