Submissions for variant NM_001040142.2(SCN2A):c.1271T>C (p.Val424Ala)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189207	SCV000242839	pathogenic	not provided	2012-11-20	criteria provided, single submitter	clinical testing	p.Val424Ala (GTG>GCG): c.1271 T>C in exon 10 of the SCN2A gene (NM_021007.2). The Val424Ala missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Val424Ala in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is conservative, as Valine and Alanine are both uncharged, non-polar amino acids. However, it alters a highly conserved position in the S6 segment of the first transmembrane domain of the protein, and multiple in silico algorithms predict it may be damaging to protein structure/function. This variant has been observed de novo without verified parentage. The variant is found in EPILEPSY panel(s).
Invitae	RCV001214974	SCV001386687	likely pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2023-03-23	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with epilepsy and/or a neurodevelopmental disorder (PMID: 29655203). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 424 of the SCN2A protein (p.Val424Ala). ClinVar contains an entry for this variant (Variation ID: 207053). 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.Val424 amino acid residue in SCN2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28709814; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Neurology Department, Shenzhen Children's Hospital	RCV001847845	SCV002099463	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-02-16	no assertion criteria provided	clinical testing

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