Submissions for variant NM_001040142.2(SCN2A):c.4503G>A (p.Met1501Ile)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Neuberg Centre For Genomic Medicine, NCGM	RCV002510724	SCV002820266	uncertain significance	Developmental and epileptic encephalopathy, 11		criteria provided, single submitter	clinical testing	The missense variant p.M1501I in SCN2A (NM_021007.2) causes a change at the same amino acid residue as a previously established pathogenic variant (M1501T). The p.M1501I variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a small physicochemical difference between methionine and isoleucine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.M1501I missense variant is predicted to be damaging by both SIFT and PolyPhen2. The methionine residue at codon 1501 of SCN2A is conserved in all mammalian species. The nucleotide c.4503 in SCN2A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003776049	SCV004575151	likely pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1501 of the SCN2A protein (p.Met1501Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1878633). 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 with a positive predictive value of 95%. This variant disrupts the p.Met1501 amino acid residue in SCN2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29933521, 31031587). 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.