Submissions for variant NM_172107.4(KCNQ2):c.868G>A (p.Gly290Ser)

dbSNP: rs1057516098

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000466204	SCV000543199	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-06-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly290 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22275249, 24318194). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 KCNQ2 protein function. ClinVar contains an entry for this variant (Variation ID: 369768). This missense change has been observed in individual(s) with early onset epileptic encephalopathy (PMID: 23621294, 23692823, 27779742). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 290 of the KCNQ2 protein (p.Gly290Ser).
GeneDx	RCV000519184	SCV000617362	pathogenic	not provided	2017-11-10	criteria provided, single submitter	clinical testing	The G290S variant in the KCNQ2 gene has been reported previously as a de novo change in multiple unrelated individuals with early onset epileptic encephalopathy (Milh et al., 2013; Kato et al., 2013; Zhang et al., 2016). The G290S variant is not observed in large population cohorts (Lek et al., 2016). The G290S 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 is predicted to be within the pore forming loop between the S5 and S6 transmembrane segments, and a different missense variant at the same position (G290D) as well as missense variants in nearby residues (T287N, R291G, R291S) have been reported in the Human Gene Mutation Database in association with epileptic encephalopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
3billion	RCV000678146	SCV002012238	pathogenic	Developmental and epileptic encephalopathy, 7	2021-10-02	criteria provided, single submitter	clinical testing	The variant has been previously reported as de novoo in at least two similarly affected unrelated individuals (PMID: 27779742, 23692823, 23621294, PS2, PS4_M). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Gly290Val, p.Gly290Asp) has been reported as pathogenic (ClinVar ID:VCV000523563.1, PMID: 23621294, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.959, 3Cnet: 0.941, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
GeneReviews	RCV000678146	SCV000484588	not provided	Developmental and epileptic encephalopathy, 7		no assertion provided	literature only	EE (epileptic encephalopathy)