NM_001134407.3(GRIN2A):c.1553G>A (p.Arg518His) AND Landau-Kleffner syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Feb 5, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000074391.42

Allele description

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

Gene:

GRIN2A:glutamate ionotropic receptor NMDA type subunit 2A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.2

Genomic location:

Preferred name:

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

HGVS:

NC_000016.10:g.9840745C>T
NG_011812.2:g.347010G>A
NM_000833.5:c.1553G>A
NM_001134407.3:c.1553G>AMANE SELECT
NM_001134408.2:c.1553G>A
NP_000824.1:p.Arg518His
NP_001127879.1:p.Arg518His
NP_001127880.1:p.Arg518His
NC_000016.9:g.9934602C>T
NG_011812.1:g.347010G>A
NM_000833.3:c.1553G>A
NM_000833.4:c.1553G>A
Q12879:p.Arg518His

Protein change:

R518H; ARG518HIS

Links:

UniProtKB: Q12879#VAR_070355; OMIM: 138253.0009; dbSNP: rs397518470

NCBI 1000 Genomes Browser:

rs397518470

Molecular consequence:

NM_000833.5:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001134407.3:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001134408.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

Condition(s)

Name:: Landau-Kleffner syndrome (FESD)
Synonyms:: Acquired aphasia with convulsive disorder; Acquired epileptiform aphasia; APHASIA, ACQUIRED, WITH EPILEPSY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009509; MedGen: C0282512; Orphanet: 1945; Orphanet: 725; Orphanet: 98818; OMIM: 245570

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000106001	OMIM	no assertion criteria provided	Pathogenic (Sep 1, 2013)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000320741	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 23933820, 24828792
SCV000638225	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 5, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27839871, 23933820, 24828792, 28492532
SCV002026437	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2019)	unknown	research	PubMed (2) [See all records that cite these PMIDs] 30544257, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains.

Swanger SA, Chen W, Wells G, Burger PB, Tankovic A, Bhattacharya S, Strong KL, Hu C, Kusumoto H, Zhang J, Adams DR, Millichap JJ, Petrovski S, Traynelis SF, Yuan H.

Am J Hum Genet. 2016 Dec 1;99(6):1261-1280. doi: 10.1016/j.ajhg.2016.10.002. Epub 2016 Nov 10.

PubMed [citation]

PMID:: 27839871
PMCID:: PMC5142120

GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.

Lesca G, Rudolf G, Bruneau N, Lozovaya N, Labalme A, Boutry-Kryza N, Salmi M, Tsintsadze T, Addis L, Motte J, Wright S, Tsintsadze V, Michel A, Doummar D, Lascelles K, Strug L, Waters P, de Bellescize J, Vrielynck P, de Saint Martin A, Ville D, Ryvlin P, et al.

Nat Genet. 2013 Sep;45(9):1061-6. doi: 10.1038/ng.2726. Epub 2013 Aug 11.

PubMed [citation]

PMID:: 23933820

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000106001.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a patient with focal epilepsy and speech disorder (FESD; 245570), with the clinical diagnosis of continuous spike and waves during slow-wave sleep syndrome, Lesca et al. (2013) identified a heterozygous c.1553G-A transition in the GRIN2A gene, resulting in an arg518-to-his (R518H) substitution at a highly conserved residue in the extracellular ligand-binding domain. The mutation was not found in the dbSNP, 1000 Genomes, or Exome Variant Server databases. The mutation was also present in the patient's brother, who had atypical rolandic epilepsy with dysphasia, and the father, who had verbal dyspraxia but no seizures. Another sib of the proband, who did not carry the mutation, had centrotemporal spikes on EEG without seizures, thus representing a phenocopy. In vitro functional expression studies in HEK293 cells showed that the mutation caused a significant increase in the open time and a decrease in the closed time of NMDA channels compared to wildtype, consistent with a modulatory effect on the excitatory postsynaptic current.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000320741.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000638225.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV002026437.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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