Submissions for variant NM_001040142.2(SCN2A):c.718G>A (p.Ala240Thr)

dbSNP: rs1064795014

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479851	SCV000570402	likely pathogenic	not provided	2016-05-19	criteria provided, single submitter	clinical testing	The A240T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, a different missense variant in the same position (A240S) has been reported previously as a de novo variant in an individual with epilepsy of infancy with migrating focal seizures (Howell et al., 2015). The A240T 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 A240T 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 occurs at a conserved position predicted to be within in the intracellular loop between the S4 and S5 transmembrane segments of the first homologous domain of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001047572	SCV001211537	likely pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2020-04-15	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with threonine at codon 240 of the SCN2A protein (p.Ala240Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of SCN2A-related conditions (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 421259). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala240 amino acid residue in SCN2A. Other variant(s) that disrupt this residue have been observed in individuals with SCN2A-related conditions (PMID: 26291284), which suggests that this may be a clinically significant amino acid residue.