Submissions for variant NM_001165963.4(SCN1A):c.3776T>C (p.Phe1259Ser)

gnomAD frequency: 0.00001  dbSNP: rs398123591

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079577	SCV000111459	uncertain significance	not provided	2013-09-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000079577	SCV000242559	likely pathogenic	not provided	2023-09-26	criteria provided, single submitter	clinical testing	Identified in multiple unrelated individuals with seizures referred for genetic testing at GeneDx (Lindy et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the transmembrane segment S2 of the third homologous domain; This variant is associated with the following publications: (PMID: 29655203, 32347949)
Invitae	RCV000701047	SCV000829829	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1259 of the SCN1A protein (p.Phe1259Ser). This variant is present in population databases (rs398123591, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of SCN1A-related conditions (PMID: 29655203; Invitae). ClinVar contains an entry for this variant (Variation ID: 93645). 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.
Genetic Services Laboratory, University of Chicago	RCV000079577	SCV002064458	likely pathogenic	not provided	2017-07-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345392	SCV002623511	uncertain significance	Inborn genetic diseases	2018-02-07	criteria provided, single submitter	clinical testing	The p.F1259S variant (also known as c.3776T>C), located in coding exon 19 of the SCN1A gene, results from a T to C substitution at nucleotide position 3776. The phenylalanine at codon 1259 is replaced by serine, an amino acid with highly dissimilar properties. A different alteration located at the same position, p.F1259C, was detected in an individual with Dravet syndrome (Moehring J et al. Epilepsia, 2013 May;54:918-26). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155068	SCV003844783	uncertain significance	not specified	2023-02-15	criteria provided, single submitter	clinical testing	Variant summary: SCN1A c.3776T>C (p.Phe1259Ser) results in a non-conservative amino acid change located in the ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249954 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3776T>C has been reported in the literature in at least one individual affected with epilepsy (Lindy_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1)/likely pathogenic (n=2), or VUS (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.