Submissions for variant NM_001165963.4(SCN1A):c.4096G>A (p.Val1366Ile)

gnomAD frequency: 0.00002  dbSNP: rs121918805

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001719807	SCV000242573	uncertain significance	not provided	2024-09-17	criteria provided, single submitter	clinical testing	In vitro functional studies indicate reduced cell surface expression, leading to a loss-of-function effect; however the effect was not as strong as other pathogenic variants (PMID: 25576396); Available evidence suggests this variant may predispose to seizures but is associated with incomplete penetrance; This substitution is predicted to be within the transmembrane segment S5 of the third homologous domain; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19586930, 23884151, 24502503, 28150151, 28664031, 32146541, 31782251, 33375447, 17507202, Shin2022, 25576396, 29655203)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001381481	SCV001579892	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1366 of the SCN1A protein (p.Val1366Ile). This variant is present in population databases (rs121918805, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant SCN1A-related conditions (PMID: 17507202). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68628). 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 expected to disrupt SCN1A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN1A function (PMID: 25576396). For these reasons, this variant has been classified as Pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003989315	SCV004806548	uncertain significance	Severe myoclonic epilepsy in infancy	2024-03-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004668767	SCV005157627	uncertain significance	Inborn genetic diseases	2024-04-22	criteria provided, single submitter	clinical testing	The c.4096G>A (p.V1366I) alteration is located in exon 21 (coding exon 21) of the SCN1A gene. This alteration results from a G to A substitution at nucleotide position 4096, causing the valine (V) at amino acid position 1366 to be replaced by an isoleucine (I). In an assay testing SCN1A function, this variant showed a functionally abnormal result (Bechi 2015). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
UniProtKB/Swiss-Prot	RCV000059506	SCV000091032	not provided	Generalized epilepsy with febrile seizures plus, type 1		no assertion provided	not provided
Channelopathy-Associated Epilepsy Research Center	RCV003989315	SCV004809299	not provided	Severe myoclonic epilepsy in infancy		no assertion provided	literature only