Submissions for variant NM_001165963.4(SCN1A):c.2977A>G (p.Ser993Gly)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002305222	SCV002590684	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2022-10-11	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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. 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. This missense change has been observed in individual(s) with clinical features of SCN1A-related conditions (Invitae). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 993 of the SCN1A protein (p.Ser993Gly).
GeneDx	RCV004725219	SCV005332770	likely pathogenic	not provided	2024-01-23	criteria provided, single submitter	clinical testing	Identified in a patient with genetic epilepsy with febrile seizures plus (GEFS+) in the published literature (PMID: 35074891); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; 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; This substitution is predicted to be in the cytoplasmic loop between the second and third homologous domains; This variant is associated with the following publications: (PMID: 35074891)