Submissions for variant NM_001040142.2(SCN2A):c.3670G>T (p.Ala1224Ser)

gnomAD frequency: 0.00001  dbSNP: rs780330020

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189139	SCV000242771	uncertain significance	not provided	2014-10-15	criteria provided, single submitter	clinical testing	p.Ala1224Ser (A1224S) GCT>TCT: c.3670 G>T in exon 19 of the SCN2A gene (NM_021007.2). The A1224S 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 A1224S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, size, and/or other properties. This substitution alters a highly conserved residue in the predicted transmembrane segment S1 in the third homologous domain of the SCN2A protein. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense mutations in nearby residues have not been reported in association with SCN2A-related disorders. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CHILD-EPI panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000706532	SCV000835589	uncertain significance	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2024-09-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1224 of the SCN2A protein (p.Ala1224Ser). This variant is present in population databases (rs780330020, gnomAD 0.006%). This missense change has been observed in individual(s) with autism spectrum disorder (PMID: 30564305). ClinVar contains an entry for this variant (Variation ID: 206989). 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 SCN2A protein function with a positive predictive value of 95%. 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.
Ambry Genetics	RCV002514052	SCV003556066	likely benign	Inborn genetic diseases	2021-06-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.