Submissions for variant NM_001040142.2(SCN2A):c.2695G>A (p.Gly899Ser)

gnomAD frequency: 0.00001  dbSNP: rs796053120

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189123	SCV000242755	pathogenic	not provided	2021-01-15	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a significant depolarizing shift of the channel activation curve compared to wild-type, consistent with loss of function (Wolff et al., 2017); Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This substitution is predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the second homologous domain; This variant is associated with the following publications: (PMID: 28379373, 32090326, 31904126, 32400968)
Ambry Genetics	RCV002426914	SCV002742694	likely pathogenic	Inborn genetic diseases	2018-02-15	criteria provided, single submitter	clinical testing	The p.G899S variant (also known as c.2695G>A), located in coding exon 15 of the SCN2A gene, results from a G to A substitution at nucleotide position 2695. The glycine at codon 899 is replaced by serine, an amino acid with similar properties. This variant was detected de novo in an individual with intractable infantile epilepsy and shown to impact sodium channel kinetics in subsequent functional studies (Wolff M et al. Brain, 2017 May;140:1316-1336). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005222816	SCV005862837	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2024-07-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 899 of the SCN2A protein (p.Gly899Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (PMID: 28379373). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 206974). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN2A function (PMID: 28379373). For these reasons, this variant has been classified as Pathogenic.
Channelopathy-Associated Epilepsy Research Center	RCV002319453	SCV002605493	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only