Submissions for variant NM_001165963.4(SCN1A):c.2576G>A (p.Arg859His)

gnomAD frequency: 0.00001  dbSNP: rs398123588

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000255810	SCV000111449	pathogenic	not provided	2013-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000255810	SCV000322016	pathogenic	not provided	2022-04-07	criteria provided, single submitter	clinical testing	Published functional studies suggest that p.R859H results in channel gating defects (Volkers et al., 2011; Volkers et al., 2013); Reported previously in an individual with generalized epilepsy with febrile seizures plus and was inherited from the patient's father who had a history of febrile seizures (Volkers et al., 2011); 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 variant is associated with the following publications: (PMID: 31782251, 29335582, 32581296, 28084635, 21864321, 33278787, 24277604, 28150151, 30446648, 33013363)
Invitae	RCV000546041	SCV000633829	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 859 of the SCN1A protein (p.Arg859His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with generalized epilepsy with febrile seizures plus (PMID: 21864321, 28084635; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 93639). 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: 21864321, 24277604). This variant disrupts the p.Arg859 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16525050, 18930999, 25576396). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781835	SCV000920184	pathogenic	Autosomal dominant epilepsy	2020-12-23	criteria provided, single submitter	clinical testing	Variant summary: SCN1A c.2576G>A (p.Arg859His) results in a non-conservative amino acid change located in the Ion transport domain (voltage sensing S4 segment of domain II) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Another missense variant affecting the same codon, namely c.2575C>T (p.Arg859Cys) has been reported with the more severe phenotype of Dravet syndrome with loss of function effects suggesting a functional relevance of this residue to protein function (Brunklaus_2020). The variant allele was found at a frequency of 8e-06 in 250370 control chromosomes. c.2576G>A has been reported in the literature in at least 3 patients with Generalized Epilepsy with Febrile Seizures Plus (GEFS+). One report showing segregation within a family, though the affected father was not genotyped (Volkers_2011) and another reporting the variant as a de novo occurrence (Myers_2017). It has also been subsequently cited by others (example, Brunklaus_2020). Additionally, a clinical lab has submitted data to Clinvar stating that the variant segregated with seizures in a single family. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect leads to mixed functional defects in Nav1.1 gating although the mutant protein is produced at normal levels (Volkers_2011; Volkers_2013). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics	RCV002247477	SCV002519030	pathogenic	Generalized epilepsy with febrile seizures plus, type 2	2022-05-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537326	SCV004102878	pathogenic	SCN1A-related disorder	2023-09-05	criteria provided, single submitter	clinical testing	The SCN1A c.2576G>A variant is predicted to result in the amino acid substitution p.Arg859His. This variant has been reported in multiple individuals with generalized epilepsy with febrile seizures plus (GEFS+) and has been repeatedly documented as having arisen de novo (Volkers et al. 2011. PubMed ID: 21864321; Myers et al. 2017. PubMed ID: 28084635; Wang et al. 2021. PubMed ID: 33278787; Zou et al. 2021. PubMed ID: 34145886; Chen et al. 2022. PubMed ID: 35571373; Çapan et al. 2023. PubMed ID: 37353388). In vitro functional studies have shown that this variant negatively impacts sodium channel function (Volkers et al. 2011. PubMed ID: 21864321; Volkers et al. 2013. PubMed ID: 24277604). This variant is reported in 0.010% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-166895946-C-T). A different missense variant at the same position (p.Arg859Cys) has also been reported as pathogenic in patients with SCN1A-related disease (Barela et al. 2006. PubMed ID: 16525050; Depienne et al. 2009. PubMed ID: 18930999; Bechi et al. 2015. PubMed ID: 25576396). Taken together, the p.Arg859His variant is interpreted as pathogenic.
Diagnostic Laboratory, Strasbourg University Hospital	RCV002274894	SCV002562848	uncertain significance	Seizure		no assertion criteria provided	clinical testing
Channelopathy-Associated Epilepsy Research Center	RCV003992180	SCV004809285	not provided	Severe myoclonic epilepsy in infancy		no assertion provided	literature only