Submissions for variant NM_001165963.4(SCN1A):c.272T>C (p.Ile91Thr)

dbSNP: rs121918734

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Bioinformatics, Peking University	RCV000059474	SCV000221870	pathogenic	Severe myoclonic epilepsy in infancy	2014-12-20	criteria provided, single submitter	research
Invitae	RCV000819332	SCV000959986	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 91 of the SCN1A protein (p.Ile91Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 18554359). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68597). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Lifecell International Pvt. Ltd	RCV003157390	SCV003845973	pathogenic	Generalized epilepsy with febrile seizures plus, type 2		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.272T>C in Exon 5 of the SCN1A gene that results in the amino acid substitution p.Ile91Thr was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic(variant ID 68597). This variant performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function(Sun H, et al., 2008). This variant has been observed in many individuals affected with Generalized epilepsy with febrile seizures reported by (Xu X et al., 2015). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
UniProtKB/Swiss-Prot	RCV000059474	SCV000090999	not provided	Severe myoclonic epilepsy in infancy		no assertion provided	not provided