Submissions for variant NM_001134407.3(GRIN2A):c.2146G>A (p.Ala716Thr)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187642	SCV000241239	likely pathogenic	not provided	2014-04-02	criteria provided, single submitter	clinical testing	p.Ala716Thr (GCC>ACC): c.2146 G>A in exon 11 of the GRIN2A gene (NM_000833.3). The A716T variant has been previously reported as a potentially deleterious variant in a family with atypical Rolandic epilepsy, verbal dyspraxia, and cognitive impairment (Lesca et al., 2013). The A716T mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. A716T 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. A716T alters a highly conserved position in the extracellular domain, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in EPILEPSY panel(s).
Eurofins Ntd Llc (ga)	RCV000187642	SCV000702017	likely pathogenic	not provided	2016-11-07	criteria provided, single submitter	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000254568	SCV001164218	pathogenic	Landau-Kleffner syndrome	2018-04-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000187642	SCV001248292	pathogenic	not provided	2016-09-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000254568	SCV002026148	likely pathogenic	Landau-Kleffner syndrome	2019-01-01	criteria provided, single submitter	research
Invitae	RCV000254568	SCV002240360	pathogenic	Landau-Kleffner syndrome	2023-08-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GRIN2A function (PMID: 27839871). 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. ClinVar contains an entry for this variant (Variation ID: 205656). This missense change has been observed in individual(s) with epilepsy (PMID: 23933820). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs762659685, gnomAD 0.01%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 716 of the GRIN2A protein (p.Ala716Thr).
GeneReviews	RCV000254568	SCV000320743	not provided	Landau-Kleffner syndrome		no assertion provided	literature only