Submissions for variant NM_001040142.2(SCN2A):c.1267G>C (p.Val423Leu)

dbSNP: rs796053180

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189206	SCV000242838	likely pathogenic	not provided	2014-03-27	criteria provided, single submitter	clinical testing	p.Val423Leu (GTG>CTG): c.1267 G>C in exon 10 of the SCN2A gene (NM_021007.2). A V423L variant that is likely pathogenic has been identified in the SCN2A gene. The V423L variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V423Lvariant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution alters a highly conserved position in transmembrane segment S6 of the first homologous domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in INFANT-EPI panel(s).
Genetics and Molecular Pathology, SA Pathology	RCV000190517	SCV002556653	pathogenic	Developmental and epileptic encephalopathy, 11	2021-08-31	criteria provided, single submitter	clinical testing	The SCN2A c.1267G>C variant is classified as PATHOGENIC (PS1, PS2, PS3, PS4-moderate, PM2) The SCN2A c.1267G>C variant is a single nucleotide change in exon 10/27 of the SCN2A gene, which is predicted to change the amino acid valine at position 423 in the protein to leucine. The same p.Val423Leu variant has been reported de novo in two unrelated patients with Ohtahara syndrome (PMID: 28379373). Patient 10 presented at day 1 with myoclonic and apnoeic seizures, while Patient 33 presented at day 6 with tonic clonic seizures. Both of these probands progressed to developing tonic and tonic-clonic seizures respectively, and EEGs showed a suppression burst pattern, and multifocal spikes. Both patients had a high pharmacoresistance including lack of response to treatment of one or more sodium channel blockers. The p.Val423Leu variant was assessed using whole cell patch-clamping in tsA201 kidney cells, which showed an increase in sodium channel activity with gain-of-function (PMID: 28379373) (PS3). This variant has been identified as de novo in this family with no family history of this condition (PS2). This variant results in the same amino acid change as another pathogenic variant, c.1267G>T, previously reported in ClinVar (Variation ID: 1072191) (PS1). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs796053180). The variant has been reported as Likely Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 207052). This variant has not been reported in HGMD. Other Literature: PMID: 31924505.
Invitae	RCV003765203	SCV004569559	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2023-04-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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 SCN2A protein function. ClinVar contains an entry for this variant (Variation ID: 207052). This missense change has been observed in individual(s) with Ohtahara syndrome (PMID: 28379373). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 423 of the SCN2A protein (p.Val423Leu).
Mendelics	RCV000190517	SCV000245403	pathogenic	Developmental and epileptic encephalopathy, 11	2023-04-28	no assertion criteria provided	clinical testing
OMIM	RCV000190517	SCV001371868	pathogenic	Developmental and epileptic encephalopathy, 11	2020-10-19	no assertion criteria provided	literature only
Channelopathy-Associated Epilepsy Research Center	RCV002319459	SCV002605492	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only