Submissions for variant NM_001040142.2(SCN2A):c.3985G>T (p.Ala1329Ser)

dbSNP: rs1057524059

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000436036	SCV000534424	pathogenic	not provided	2016-12-20	criteria provided, single submitter	clinical testing	The A1329S variant in the SCN2A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The A1329S variant was not observed in approximately 6500 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 A1329S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution is within the intracellular loop between the S4 and S5 transmembrane segments of the third homologous domain and occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. As an alternate mechanism, multiple in silico algorithms predict that c.3985 G>T (aka A1329S) might create a cryptic splice acceptor site in exon 22 which may supplant the natural acceptor site. However, in the absence of RNA/functional studies, the actual effect of c.3985 G>T in this individual is unknown. Missense variants in nearby residues (V1326L, V1326D, L1330F) have been reported in the Human Gene Mutation Database in association with SCN2A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret A1329S as a pathogenic variant.