ClinVar Miner

Submissions for variant NM_020822.3(KCNT1):c.1193G>A (p.Arg398Gln) (rs397515407)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000553512 SCV000992727 pathogenic Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2018-10-12 criteria provided, single submitter clinical testing
GeneDx RCV000412976 SCV000490582 pathogenic not provided 2018-04-20 criteria provided, single submitter clinical testing The R398Q pathogenic variant in the KCNT1 gene has been reported multiple times previously in association with KCNT1-related disorders (Heron et al., 2012; Moller et al., 2015; Allen et al., 2016). Functional studies of the R398Q variant indicate that it results in a gain of function that causes an increase in current amplitude and altered channel activation and deactivation kinetics (Milligan et al., 2014). The R398Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R398Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species.
GeneReviews RCV000032799 SCV000211889 pathogenic Epilepsy, nocturnal frontal lobe, 5 2015-02-19 no assertion criteria provided literature only
Invitae RCV000553512 SCV000652903 pathogenic Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2018-06-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 398 of the KCNT1 protein (p.Arg398Gln). 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 reported in individuals affected with autosomal dominant nocturnal frontal lobe epilepsy (ADFLE), malignant migrating partial seizures of infancy (MMPSI), malignant migrating focal seizures of infancy (MMFSI), and focal epilepsy and has been shown to co-segregate with disease in 3 affected families (PMID: 23086396, 25482562, 26122718, 26140313, 25482562). This variant has also been reported to be de novo in 1 individual affected with MMPSI (PMID: 26648591). ClinVar contains an entry for this variant (Variation ID: 39599). Experimental studies have shown that this missense change alters the activation kinetics and conductance of the KCNT1 channel (PMID: 24591078). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000032799 SCV000056567 pathogenic Epilepsy, nocturnal frontal lobe, 5 2012-11-01 no assertion criteria provided literature only
Oxford Medical Genetics Laboratories,Oxford University Hospitals NHS Foundation Trust RCV000787272 SCV000926200 pathogenic Early infantile epileptic encephalopathy 14 2019-05-03 no assertion criteria provided clinical testing

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