Submissions for variant NM_020822.3(KCNT1):c.3149C>T (p.Thr1050Ile)

gnomAD frequency: 0.00003  dbSNP: rs1313669242

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001270711	SCV001451456	uncertain significance	Autosomal dominant nocturnal frontal lobe epilepsy 5	2019-06-17	criteria provided, single submitter	clinical testing	The KCNT1 c.3149C>T (p.Thr1050Ile) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The p.Thr1050Ile variant is reported at a frequency of 0.000009 in the European (Non-Finnish) population of the Genome Aggregation Database though this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Based on the limited evidence, the p.Thr1050Ile variant is classified as a variant of uncertain significance for KCNT1-realted epilepsy.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001362103	SCV001558105	uncertain significance	Developmental and epileptic encephalopathy, 14; Autosomal dominant nocturnal frontal lobe epilepsy 5	2024-06-03	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1050 of the KCNT1 protein (p.Thr1050Ile). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 989244). 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%. 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.
GeneDx	RCV001751539	SCV001996034	uncertain significance	not provided	2019-09-12	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV002271202	SCV002554813	uncertain significance	Developmental and epileptic encephalopathy, 14	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001270711	SCV002554815	uncertain significance	Autosomal dominant nocturnal frontal lobe epilepsy 5	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002322175	SCV002608591	uncertain significance	Inborn genetic diseases	2017-07-31	criteria provided, single submitter	clinical testing	The p.T1050I variant (also known as c.3149C>T), located in coding exon 27 of the KCNT1 gene, results from a C to T substitution at nucleotide position 3149. The threonine at codon 1050 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.