Submissions for variant NM_001165963.4(SCN1A):c.4793A>T (p.Tyr1598Phe)

gnomAD frequency: 0.00001  dbSNP: rs377325221

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188979	SCV000242610	uncertain significance	not provided	2023-01-05	criteria provided, single submitter	clinical testing	Identified in multiple patients with epilepsy, as well as another individual with autism and schizophrenia referred for genetic testing at GeneDx and in published literature (Lindy et al., 2018; Till et al., 2020; Papp-Hertelendi et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This substitution is predicted to be within the intracellular loop between the S2 and S3 transmembrane segments of the fourth homologous domain; This variant is associated with the following publications: (PMID: 29655203, 31765958, 30060894)
Ambry Genetics	RCV002317152	SCV000851064	uncertain significance	Inborn genetic diseases	2016-06-21	criteria provided, single submitter	clinical testing	The p.Y1598F variant (also known as c.4793A>T), located in coding exon 25 of the SCN1A gene, results from an A to T substitution at nucleotide position 4793. The tyrosine at codon 1598 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs377325221. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied and 0.01% (1/8600) European American alleles. Allele frequency data for this nucleotide position is not currently available from the 1000 Genomes Project. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this variant remains unclear.
Eurofins Ntd Llc (ga)	RCV000188979	SCV000863017	uncertain significance	not provided	2018-08-24	criteria provided, single submitter	clinical testing
Invitae	RCV000812724	SCV000953047	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2023-06-07	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1598 of the SCN1A protein (p.Tyr1598Phe). This variant is present in population databases (rs377325221, gnomAD 0.002%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 206850). This missense change has been observed in individual(s) with clinical features of SCN1A-related conditions and/or Dravet syndrome (PMID: 29655203, 31765958).