Submissions for variant NM_001040142.2(SCN2A):c.3961G>C (p.Glu1321Gln)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002881900	SCV003241503	likely pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2023-03-23	criteria provided, single submitter	clinical testing	This variant disrupts the p.Glu1321 amino acid residue in SCN2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25982755, 30619928). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. 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: 2036225). This variant has not been reported in the literature in individuals affected with SCN2A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 1321 of the SCN2A protein (p.Glu1321Gln).