rs762659685
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1_ModeratePM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_001134407.3(GRIN2A):c.2146G>A(p.Ala716Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A716D) has been classified as Uncertain significance.
Frequency
Consequence
NM_001134407.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GRIN2A | NM_001134407.3 | c.2146G>A | p.Ala716Thr | missense_variant | 10/13 | ENST00000330684.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GRIN2A | ENST00000330684.4 | c.2146G>A | p.Ala716Thr | missense_variant | 10/13 | 1 | NM_001134407.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461306Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726980
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Landau-Kleffner syndrome Pathogenic:3Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | research | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 03, 2023 | 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Apr 16, 2018 | - - |
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 07, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 02, 2014 | 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2016 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 08, 2024 | The c.2146G>A (p.A716T) alteration is located in coding exon 9 of the GRIN2A gene. This alteration results from a G to A substitution at nucleotide position 2146, causing the alanine (A) at amino acid position 716 to be replaced by a threonine (T). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported as a heterozygous de novo finding in multiple unrelated patients with clinical features of GRIN2A-related speech disorders and epilepsy (Li, 2020; Lee, 2021. external communications). This has also been shown to segregate with disease in a family with atypical rolandic epilepsy, verbal dyspraxia, cognitive impairment of variable degrees (Lesca, 2013). 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 the available evidence, this alteration is classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at