ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000412976 SCV000490582 pathogenic not provided 2019-07-01 criteria provided, single submitter clinical testing Published functional studies demonstrate that R398Q results in a gain of function that causes an increase in current amplitude and altered channel activation and deactivation kinetics (Milligan et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28488083, 24591078, 25482562, 23086396, 26122718, 26648591, 26140313, 29291456, 31872048, 31130284, 32167590, 31216405)
Invitae RCV000553512 SCV000652903 pathogenic Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2020-06-16 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.
Baylor Genetics RCV000553512 SCV000992727 pathogenic Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2018-10-12 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000032799 SCV001440375 likely pathogenic Epilepsy, nocturnal frontal lobe, 5 2020-09-07 criteria provided, single submitter clinical testing
Centre for Inherited Metabolic Diseases, Karolinska University Hospital RCV001375627 SCV001572550 pathogenic Epilepsy syndrome 2021-04-25 criteria provided, single submitter clinical testing
OMIM RCV000032799 SCV000056567 pathogenic Epilepsy, nocturnal frontal lobe, 5 2012-11-01 no assertion criteria provided literature only
GeneReviews RCV000032799 SCV000211889 pathogenic Epilepsy, nocturnal frontal lobe, 5 2015-02-19 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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