Submissions for variant NM_001040142.2(SCN2A):c.3955C>T (p.Arg1319Trp)

dbSNP: rs190111194

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469153	SCV000551882	likely pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2022-06-23	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 410982). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg1319 amino acid residue in SCN2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15048894, 18479388, 28379373). 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. This missense change has been observed in individual(s) with West syndrome (PMID: 27781031). In at least one individual the variant was observed to be de novo. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1319 of the SCN2A protein (p.Arg1319Trp). This variant is present in population databases (rs190111194, gnomAD 0.0009%).
Neuberg Centre For Genomic Medicine, NCGM	RCV002510575	SCV002820103	pathogenic	Developmental and epileptic encephalopathy, 11		criteria provided, single submitter	clinical testing	The missense variant p.R1319W in SCN2A (NM_021007.3) causes the same amino acid change as a previously established pathogenic variant. This variant has been observed to be de novo in an individual affected with West syndrome (Møller RS et al). The missense variant c.3955C>T (p.R1319W) in SCN2A (NM_021007.3) is observed in 1/113374 (0.0009%) alleles from individuals of European (Non-Finnish) background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state. It has been submitted to ClinVar as Pathogenic.The p.R1319W missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 1319 of SCN2A is conserved in all mammalian species. The nucleotide c.3955 in SCN2A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001270400	SCV001450683	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11; Episodic ataxia, type 9	2020-04-16	no assertion criteria provided	clinical testing