Submissions for variant NM_001040142.2(SCN2A):c.2995G>A (p.Glu999Lys) (rs796053126)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189130	SCV000242762	pathogenic	not provided	2017-07-25	criteria provided, single submitter	clinical testing	The E999K variant has been reported previously as a de novo variant in multiple individuals with Ohtahara syndrome, early infantile epileptic encephaopathy, and severe intellectual disability (Nakamura et al., 2013, Allen et al., 2015, Trump et al., 2016). The E999K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E999K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution alters a conserved position in the intracellular loop between the second and third transmembrane domains (Shi et al., 2012), and other missense variants have been reported in this region of the protein in association with epilepsy. A missense change at the same codon (E999V) has been reported in association with SCN2A-related disorder (Stenson et al., 2014, Trump et al., 2016). In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, E999K is considered a pathogenic variant.
NeuroMeGen,Hospital Clinico Santiago de Compostela	RCV000496128	SCV000586737	likely pathogenic	Early infantile epileptic encephalopathy 11		criteria provided, single submitter	clinical testing
Invitae	RCV000814425	SCV000954835	pathogenic	Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11	2018-07-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 999 of the SCN2A protein (p.Glu999Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with early onset epileptic encephalopathy; in many of these cases, it was observed to be de novo (PMID: 26993267, 28379373, 27867041, 26648591, 23935176). ClinVar contains an entry for this variant (Variation ID: 206981). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.