Submissions for variant NM_001134407.3(GRIN2A):c.2179G>A (p.Ala727Thr)

dbSNP: rs1555488144

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000996205	SCV001150799	likely pathogenic	not provided	2018-10-01	criteria provided, single submitter	clinical testing
Invitae	RCV001360564	SCV001556489	pathogenic	Landau-Kleffner syndrome	2023-09-05	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 727 of the GRIN2A protein (p.Ala727Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of GRIN2A-related conditions (PMID: 23933819, 28109652; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 433124). 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. Experimental studies have shown that this missense change affects GRIN2A function (PMID: 27839871). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000996205	SCV001786352	pathogenic	not provided	2023-05-14	criteria provided, single submitter	clinical testing	Identified in individuals with epilepsy in the published literature with either unknown segregation or inheritance from an unaffected parent (Lemke et al., 2013; von Stulpnagel et al., 2017); Published functional studies demonstrate reduced glutamate potency compared to wild type (Swanger et al., 2016); 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: 23933819, 29358611, 28109652, 35936491, 36516565, 27839871)
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV001360564	SCV004042680	pathogenic	Landau-Kleffner syndrome		criteria provided, single submitter	clinical testing
Bioinformatics Core, Luxembourg Center for Systems Biomedicine	RCV000656045	SCV000588321	pathogenic	Childhood epilepsy with centrotemporal spikes	2017-01-01	no assertion criteria provided	case-control	CAADphred>15
Gene Discovery Core-Manton Center, Boston Children's Hospital	RCV001360564	SCV001768740	pathogenic	Landau-Kleffner syndrome	2020-02-14	no assertion criteria provided	research	This variant is interpreted as Pathogenic for epilepsy and episodic atazia; Autosomal Dominant. PS2-De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. PS3- Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product, PMID:27839871. PM1- Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. PM2- Absent from controls in gnomad.PP3- Multiple lines of computational evidence support a deleterious effect on the gene or gene product. (conservation, evolutionary, splicing impact, etc.). PP5- Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation (PMID: 23933819, PMID: 28109652)