Submissions for variant NM_001040142.2(SCN2A):c.4879G>A (p.Val1627Met)

dbSNP: rs796053156

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189170	SCV000242802	uncertain significance	not specified	2013-10-24	criteria provided, single submitter	clinical testing	p.Val1627Met (GTG>ATG): c.4879 G>A in exon 27 of the SCN2A gene (NM_021007.2). The Val627Met missense change 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. This variant is a conservative substitution, as Valine and Methionine are both uncharged, non-polar amino acids. It alters a highly conserved position in the S4 segment of the fourth transmembrane domain of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether Val627Met is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000640616	SCV000762210	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2022-10-25	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as 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: 207018). This missense change has been observed in individual(s) with epilepsy and SCN2A-related disorders (PMID: 28379373; Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1627 of the SCN2A protein (p.Val1627Met).
CeGaT Center for Human Genetics Tuebingen	RCV001090354	SCV001245855	pathogenic	not provided	2018-11-01	criteria provided, single submitter	clinical testing