Submissions for variant NM_020822.3(KCNT1):c.2800G>A (p.Ala934Thr)

dbSNP: rs397515403

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000791441	SCV000290487	pathogenic	Developmental and epileptic encephalopathy, 14; Autosomal dominant nocturnal frontal lobe epilepsy 5	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 934 of the KCNT1 protein (p.Ala934Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early-onset epileptic encephalopathy, including malignant migrating partial seizures of infancy (PMID: 23086397, 25482562, 26122718, 26140313, 26993267). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 39594). 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: 23086397, 24591078). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000494477	SCV000582546	pathogenic	not provided	2022-04-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as the p.A934T variant causes a marked increase in KCNT1 protein function; the mutant channel activates significantly more quickly than wild-type channels with greater current amplitude (Barcia et al., 2012; Milligan et al., 2014; Kim et al., 2014); Not observed in large population cohorts (gnomAD); 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: 23599387, 26122718, 23086397, 25482562, 27620904, 26785903, 26441003, 26140313, 26740507, 27779742, 27064559, 29390993, 30182498, 31054490, 31487502, 30847371, 30782581, 31872048, 31532509, 32139178, 24591078, 29100083, 32167590)
Baylor Genetics	RCV000032794	SCV000807331	pathogenic	Developmental and epileptic encephalopathy, 14	2023-03-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000494477	SCV001247128	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	KCNT1: PS2, PM1, PM2, PS4:Moderate, PS3:Supporting
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000032794	SCV001786703	pathogenic	Developmental and epileptic encephalopathy, 14		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000494477	SCV002023233	pathogenic	not provided	2019-09-26	criteria provided, single submitter	clinical testing
OMIM	RCV000032794	SCV000056562	pathogenic	Developmental and epileptic encephalopathy, 14	2012-11-01	no assertion criteria provided	literature only