Submissions for variant NM_001040142.2(SCN2A):c.3670G>T (p.Ala1224Ser) (rs780330020)

Total submissions: 2

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).
Invitae	RCV000706532	SCV000835589	uncertain significance	Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11	2018-03-16	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with serine at codon 1224 of the SCN2A protein (p.Ala1224Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs780330020, ExAC 0.006%). This variant has not been reported in the literature in individuals with SCN2A-related disease. ClinVar contains an entry for this variant (Variation ID: 206989). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.