Submissions for variant NM_001165963.4(SCN1A):c.5771G>A (p.Arg1924His)

gnomAD frequency: 0.00001  dbSNP: rs3749029

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189021	SCV000242652	uncertain significance	not provided	2023-08-08	criteria provided, single submitter	clinical testing	Reported previously in an individual with epilepsy of infancy with migrating focal seizures; however, it was also identified in this individual's unaffected father and multiple unaffected siblings. Additionally, this individual also had two variants identified in the SLC12A5 gene (Saito et al., 2017).; Not observed at significant frequency in large population cohorts (gnomAD); This substitution is predicted to be within the C-terminal cytoplasmic domain; 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 variant is associated with the following publications: (PMID: 23586701, 28477354, 21713554)
Invitae	RCV003588595	SCV004285074	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2023-12-23	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 1924 of the SCN1A protein (p.Arg1924His). This variant is present in population databases (rs3749029, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of SCN1A-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 206881). 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%. This variant disrupts the p.Arg1924 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in individuals with SCN1A-related conditions (PMID: 35571373), which suggests that this may be a clinically significant amino acid residue. 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.