Submissions for variant NM_001165963.4(SCN1A):c.4970G>A (p.Arg1657His)

dbSNP: rs121917994

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001229900	SCV001402362	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-10-07	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 1657 of the SCN1A protein (p.Arg1657His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early onset epilepsy and/or neurological and developmental disorders (PMID: 17347258, 32581362). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68559). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1657 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in individuals with SCN1A-related conditions (PMID: 14672992), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV004760364	SCV005368320	pathogenic	Generalized epilepsy with febrile seizures plus, type 2	2024-08-21	criteria provided, single submitter	clinical testing	Criteria applied: PS1,PM5_STR,PS4_MOD,PM1,PM2,PP3
GeneDx	RCV004786353	SCV005401331	likely pathogenic	not provided	2024-05-13	criteria provided, single submitter	clinical testing	Not observed 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 within the intracellular loop between the S4 and S5 transmembrane segments of the fourth homologous domain; This variant is associated with the following publications: (PMID: 33238377, 35918039, 32581362, 35074891, 21719429, 17347258, 37541188, 16380441, 14672992)
UniProtKB/Swiss-Prot	RCV000059434	SCV000090958	not provided	Focal epilepsy		no assertion provided	not provided
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003955	SCV001161945	likely pathogenic	Autism; Focal-onset seizure; Microcephaly		no assertion criteria provided	research