Submissions for variant NM_001040142.2(SCN2A):c.1199C>G (p.Thr400Arg)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414166	SCV000491868	likely pathogenic	not provided	2016-12-09	criteria provided, single submitter	clinical testing	The T400R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant 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. The T400R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a conserved position in mammals that is predicted to be within the pore forming loop between the S5 and S6 transmembrane segments of the first homologous domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in Human Gene Mutation Database in association with SCN2A-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000813874	SCV000954255	uncertain significance	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2018-11-09	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with arginine at codon 400 of the SCN2A protein (p.Thr400Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SCN2A-related disease. ClinVar contains an entry for this variant (Variation ID: 373283). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001004676	SCV001164130	likely pathogenic	Developmental and epileptic encephalopathy, 11	2017-05-30	criteria provided, single submitter	clinical testing
GenomeConnect - Simons Searchlight	RCV001265504	SCV001443648	likely pathogenic	Complex neurodevelopmental disorder	2017-03-10	no assertion criteria provided	provider interpretation	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2017-03-10 and interpreted as Likely Pathogenic. Variant was initially reported on 2016-11-14 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar.