Submissions for variant NM_001040142.2(SCN2A):c.5318C>T (p.Ala1773Val)

dbSNP: rs1553463602

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000623334	SCV000741224	pathogenic	Inborn genetic diseases	2015-12-10	criteria provided, single submitter	clinical testing
Invitae	RCV001214076	SCV001385739	likely pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2020-03-11	criteria provided, single submitter	clinical testing	This variant has been observed in individuals affected with autism spectrum disorder and seizures (PMID: 27824329, 28379373). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 520893). 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.Ala1773 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 1773 of the SCN2A protein (p.Ala1773Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine.
GeneDx	RCV002051868	SCV002319076	pathogenic	not provided	2022-03-24	criteria provided, single submitter	clinical testing	A different missense change at this residue (A1773T) has been reported as likely pathogenic in ClinVar and pathogenic in the published literature in association with SCN2A-related disorders (ClinVar SCV000551877.4; Miao et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the transmembrane segment S6 of the fourth homologous domain; This variant is associated with the following publications: (PMID: 32090326, 28379373, 31105003, 32400968, 27824329, 31785789)
GenomeConnect - Simons Searchlight	RCV001265277	SCV001443394	pathogenic	Complex neurodevelopmental disorder	2016-05-04	no assertion criteria provided	provider interpretation	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-05-04 and interpreted as Pathogenic. Variant was initially reported on 2016-01-18 by GTR ID of laboratory name 61756. The reporting laboratory might also submit to ClinVar.