Submissions for variant NM_020822.3(KCNT1):c.3598C>T (p.Arg1200Cys)

gnomAD frequency: 0.00012  dbSNP: rs372028322

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000282131	SCV000329375	uncertain significance	not provided	2016-07-19	criteria provided, single submitter	clinical testing	The R1200C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1200C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with KCNT1-related disease (Stenson et al., 2014). Additionally, the R1200C variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project; but the 1000 Genomes Project reports R1200C was observed in 2/206 (1.0%) alleles from individuals of Gujarati Indian background, indicating it may be a rare (benign) variant in this population. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000464290	SCV000553822	uncertain significance	Developmental and epileptic encephalopathy, 14; Autosomal dominant nocturnal frontal lobe epilepsy 5	2024-01-17	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 1200 of the KCNT1 protein (p.Arg1200Cys). This variant is present in population databases (rs372028322, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with KCNT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 279822). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV002270199	SCV002554849	uncertain significance	Developmental and epileptic encephalopathy, 14	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270200	SCV002554850	uncertain significance	Autosomal dominant nocturnal frontal lobe epilepsy 5	2022-03-15	criteria provided, single submitter	clinical testing