Submissions for variant NM_020822.3(KCNT1):c.2782C>T (p.Arg928Cys)

gnomAD frequency: 0.00001  dbSNP: rs397515405

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001044165	SCV001207946	pathogenic	Developmental and epileptic encephalopathy, 14; Autosomal dominant nocturnal frontal lobe epilepsy 5	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 928 of the KCNT1 protein (p.Arg928Cys). This variant is present in population databases (rs397515405, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal dominant nocturnal frontal lobe epilepsy (PMID: 23086396, 26122718). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39597). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNT1 protein function. Experimental studies have shown that this missense change affects KCNT1 function (PMID: 24591078, 25482562). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001091224	SCV001247127	pathogenic	not provided	2018-11-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000032797	SCV001523119	pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy 5	2020-07-07	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV001091224	SCV001716060	pathogenic	not provided	2020-11-24	criteria provided, single submitter	clinical testing	PS3, PS4_moderate, PM2, PP1, PP3, PP4
GeneDx	RCV001091224	SCV001986276	pathogenic	not provided	2022-05-31	criteria provided, single submitter	clinical testing	Functional studies indicate that the R928C variant results in a gain of function in KCNT1 channel properties (Evely et al., 2017; Milligan et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25568878, 24395520, 26740507, 24591078, 25482562, 29037447, 26140313, 26122718, 28488083, 29196578, 27029629, 20301348, 28761347, 31208268, 30804880, 30112700, Cole2021[functionalstudy], Khamdiyeva2021[casereport], 28366665, 23086396)
Mendelics	RCV002247410	SCV002516613	pathogenic	Developmental and epileptic encephalopathy, 14	2022-05-04	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000032797	SCV002549823	pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy 5	2022-06-15	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS3, PS4, PP3, PP4
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002247410	SCV002557593	pathogenic	Developmental and epileptic encephalopathy, 14	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with nocturnal frontal lobe epilepsy 5 (MIM#615005) and early infantile epileptic encephalopathy 14, (MIM#614959) (PMID: 24591078). Both phenotypes have been shown to be caused by the same variant within the same family (GeneReview). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 26122718). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with nocturnal frontal lobe epilepsy (ClinVar, PMID: 23086396, 26122718). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with nocturnal frontal lobe epilepsy in one family (PMID: 23086396). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies using patch clamp analysis showed that mutant protein causes an increased current amplitude and modulated channel activation and deactivation kinetics. However, patch clamp assays have been shown to be unreliable, therefore results from these studies are used with caution during variant classification (PMID: 24591078). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000032797	SCV000056565	pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy 5	2012-11-01	no assertion criteria provided	literature only
GeneReviews	RCV000032797	SCV000211892	not provided	Autosomal dominant nocturnal frontal lobe epilepsy 5		no assertion provided	literature only
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000032797	SCV001752425	pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy 5		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001091224	SCV001930182	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001091224	SCV001955840	pathogenic	not provided		no assertion criteria provided	clinical testing