Submissions for variant NM_001134407.3(GRIN2A):c.2069C>T (p.Thr690Met)

dbSNP: rs1445802934

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000513348	SCV000608751	uncertain significance	not provided	2017-04-01	criteria provided, single submitter	clinical testing
NeuroMeGen, Hospital Clinico Santiago de Compostela	RCV000585851	SCV000693769	likely pathogenic	Landau-Kleffner syndrome	2018-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624530	SCV000740721	uncertain significance	Inborn genetic diseases	2024-11-06	criteria provided, single submitter	clinical testing	The c.2069C>T (p.T690M) alteration is located in exon 11 (coding exon 9) of the GRIN2A gene. This alteration results from a C to T substitution at nucleotide position 2069, causing the threonine (T) at amino acid position 690 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of <0.001% (1/251308) total alleles studied. The highest observed frequency was 0.001% (1/113654) of European (non-Finnish) alleles. This variant has been determined to be the result of a de novo mutation or has been observed to be heterozygous in individuals with features consistent with GRIN2A-related speech disorders and epilepsy (Fernandez, 2019; Ambry internal data; external communication). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000585851	SCV000829041	pathogenic	Landau-Kleffner syndrome	2024-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 690 of the GRIN2A protein (p.Thr690Met). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with epilepsy (PMID: 31780880). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 444362). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GRIN2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV001375043	SCV001334406	likely pathogenic	Neurodevelopmental disorder	2021-04-01	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000585851	SCV004013643	pathogenic	Landau-Kleffner syndrome		criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.61; 3Cnet: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GRIN2A related disorder (ClinVar ID: VCV000444362 / PMID: 31780880). The variant has been previously reported as de novo in a similarly affected individual (PMID: 31780880). A different missense change at the same codon (p.Thr690Lys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000981282). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.