Submissions for variant NM_001040142.2(SCN2A):c.718G>T (p.Ala240Ser)

dbSNP: rs1064795014

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001755556	SCV002005106	pathogenic	not provided	2020-12-30	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32090326, 26291284)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471151	SCV002768461	pathogenic	Developmental and epileptic encephalopathy, 11	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with SCN2A-related disorders. Missense variants causing a gain in function, result in either developmental and epileptic encephalopathy 11 (MIM#613721) or benign familial infantile seizures 3 (MIM#607745). Variants displaying a loss of function effect cause autism spectrum disorder and/or intellectual disability, with or without childhood-onset seizures; the functional consequence of truncating variants is unknown (OMIM, PMID: 29691040). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to serine. (I) 0254 - This variant is potentially mosaic. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. These alternative changes (p.(Ala240Thr), p.(Ala240Phe), p.(Ala240Val)) have been reported several times as likely pathogenic or pathogenic in individuals with SCN2A-related conditions. In most of these individuals, the variant was de novo (ClinVar, PMID: 29655203). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). This individual was reported in a peer-reviewed publication, where the variant was confirmed to have arisen de novo (PMID: 26291284). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV002544193	SCV003525054	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2023-07-10	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 240 of the SCN2A protein (p.Ala240Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SCN2A-related conditions (PMID: 26291284; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1318908). 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. This variant disrupts the p.Ala240 amino acid residue in SCN2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.