Submissions for variant NM_001134407.3(GRIN2A):c.1553G>A (p.Arg518His)

dbSNP: rs397518470

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000379543	SCV000329757	pathogenic	not provided	2023-01-20	criteria provided, single submitter	clinical testing	Reported previously in a family with verbal dyspraxia, atypical Rolandic epilepsy, and continuous spike and wave during slow-wave sleep syndrome, and in an individual with Landau-Kleffner syndrome (Lesca et al., 2013; Conroy et al., 2014); Published functional studies show that the R518H variant impacts NMDA receptor function (Lesca et al., 2013; Sibarov et al., 2017)); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24828792, no PMID, 23933820, 27839871, 28611597, 27683935, 30544257, 33240831, 32102377, 32144935, 29976148, 33823469, 32877683, Elmasri2020[article])
Invitae	RCV000074391	SCV000638225	pathogenic	Landau-Kleffner syndrome	2022-02-05	criteria provided, single submitter	clinical testing	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 GRIN2A protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg518 amino acid residue in GRIN2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GRIN2A function (PMID: 23933820, 27839871). ClinVar contains an entry for this variant (Variation ID: 88732). This missense change has been observed in individuals with Landau-Kleffner syndrome and verbal dyspraxia, atypical Rolandic epilepsy, and continuous spike and wave during slow-wave sleep syndrome (PMID: 23933820, 24828792). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 518 of the GRIN2A protein (p.Arg518His).
Institute of Human Genetics, University of Leipzig Medical Center	RCV000074391	SCV002026437	likely pathogenic	Landau-Kleffner syndrome	2019-01-01	criteria provided, single submitter	research
OMIM	RCV000074391	SCV000106001	pathogenic	Landau-Kleffner syndrome	2013-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000074391	SCV000320741	not provided	Landau-Kleffner syndrome		no assertion provided	literature only