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

dbSNP: rs397515407

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000412976	SCV000490582	pathogenic	not provided	2022-02-01	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); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28488083, 24591078, 25482562, 23086396, 26122718, 26648591, 26140313, 31872048, 31130284, 32167590, 31216405, 29291456, 28252636, 33726816)
Invitae	RCV000553512	SCV000652903	pathogenic	Developmental and epileptic encephalopathy, 14; Autosomal dominant nocturnal frontal lobe epilepsy 5	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 398 of the KCNT1 protein (p.Arg398Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) 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 (PMID: 23086396, 25482562, 26122718, 26140313, 26648591). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39599). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNT1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects KCNT1 function (PMID: 24591078). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000553512	SCV000992727	pathogenic	Developmental and epileptic encephalopathy, 14; Autosomal dominant nocturnal frontal lobe epilepsy 5	2018-10-12	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000032799	SCV001440375	likely pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy 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
Mendelics	RCV000787272	SCV002516611	pathogenic	Developmental and epileptic encephalopathy, 14	2022-05-04	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000787272	SCV002577445	pathogenic	Developmental and epileptic encephalopathy, 14	2022-08-24	criteria provided, single submitter	clinical testing	PM2, PM5, PP5
MGZ Medical Genetics Center	RCV000032799	SCV002580571	likely pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy 5	2022-01-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000553512	SCV002797633	pathogenic	Developmental and epileptic encephalopathy, 14; Autosomal dominant nocturnal frontal lobe epilepsy 5	2022-03-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398586	SCV004104638	pathogenic	KCNT1-related condition	2023-04-13	criteria provided, single submitter	clinical testing	The KCNT1 c.1193G>A variant is predicted to result in the amino acid substitution p.Arg398Gln. This variant has been reported in at least 14 individuals with KCNT1-related epilepsy (see for example, Heron et al. 2012. PubMed ID: 23086396; Kim et al. 2014. PubMed ID: 25482562; Møller et al. 2015. PubMed ID: 26122718; Allen et al. 2016. PubMed ID: 26648591; Barcia et al. 2019. PubMed ID: 31872048) and is documented to have occurred de novo in at least 3 cases (Abdelnour et al. 2018. PubMed ID: 29291456; Monies et al. 2019. PubMed ID: 31130284; Borlot et al. 2020. PubMed ID: 32167590). In vitro experimental studies suggest that this variant impacts protein function (Milligan et al. 2014. PubMed ID: 24591078). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare or absent in the general population. Taken together, this variant is interpreted as pathogenic.
OMIM	RCV000032799	SCV000056567	pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy 5	2012-11-01	no assertion criteria provided	literature only
GeneReviews	RCV000032799	SCV000211889	not provided	Autosomal dominant nocturnal frontal lobe epilepsy 5		no assertion provided	literature only
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	RCV000787272	SCV000926200	pathogenic	Developmental and epileptic encephalopathy, 14	2019-05-03	no assertion criteria provided	clinical testing