Submissions for variant NM_001165963.4(SCN1A):c.1193C>T (p.Thr398Met)

gnomAD frequency: 0.00001  dbSNP: rs774937055

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188865	SCV000242495	uncertain significance	not provided	2013-08-28	criteria provided, single submitter	clinical testing	p.Thr398Met (ACG>ATG): c.1193 C>T in exon 9 of the SCN1A gene (NM_001165963.1) The Thr398Met missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution of a polar Threonine residue with a non-polar Methionine residue at a position that is conserved through mammals. The variant occurs between the S5 and S6 segments in the first transmembrane domain and many other missense mutations have been reported in this region associated with epilepsy. In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Thr398Met is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Illumina Laboratory Services, Illumina	RCV001134812	SCV001294571	uncertain significance	Generalized epilepsy with febrile seizures plus, type 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001134813	SCV001294572	uncertain significance	Migraine, familial hemiplegic, 3	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001320100	SCV001510873	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 398 of the SCN1A protein (p.Thr398Met). This variant is present in population databases (rs774937055, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant genetic epilepsy with febrile seizures plus (PMID: 31875159, 34489640, 35663268, 36158059; Invitae). ClinVar contains an entry for this variant (Variation ID: 206762). 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%. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV001775093	SCV002011963	uncertain significance	Severe myoclonic epilepsy in infancy	2021-10-02	criteria provided, single submitter	clinical testing	The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000212) but it is observed in unaffected individuals (3billion dataset). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.706, 3Cnet: 0.910). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Neuberg Centre For Genomic Medicine, NCGM	RCV001775093	SCV004047413	uncertain significance	Severe myoclonic epilepsy in infancy		criteria provided, single submitter	clinical testing	The missense variant c.1193C>T in SCN1A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This (p.Thr398Met) variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. The p.Thr398Met variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.002124% in gnomAD database. This variant has been reported to the ClinVar database as Likely Pathogenic; Variant of Uncertain Significance (VUS). The amino acid change p.Thr398Met in SCN1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Thr at position 398 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).