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).
ClinVar Genomic variation as it relates to human health
NM_001134407.3(GRIN2A):c.1553G>A (p.Arg518His)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(5)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001134407.3(GRIN2A):c.1553G>A (p.Arg518His)
Variation ID: 88732 Accession: VCV000088732.10
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p13.2 16: 9840745 (GRCh38) [ NCBI UCSC ] 16: 9934602 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 11, 2015 Feb 20, 2024 Jan 20, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001134407.3:c.1553G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001127879.1:p.Arg518His missense NM_000833.5:c.1553G>A NP_000824.1:p.Arg518His missense NM_001134408.2:c.1553G>A NP_001127880.1:p.Arg518His missense NC_000016.10:g.9840745C>T NC_000016.9:g.9934602C>T NG_011812.2:g.347010G>A Q12879:p.Arg518His - Protein change
- R518H
- Other names
- -
- Canonical SPDI
- NC_000016.10:9840744:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
loss_of_function_variant; Sequence Ontology [ SO:0002054]
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| GRIN2A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2090 | 2142 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 5, 2022 | RCV000074391.43 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 20, 2023 | RCV000379543.12 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jan 01, 2019)
|
criteria provided, single submitter
Method: research
|
Landau-Kleffner syndrome
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002026437.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
|
|
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Pathogenic
(Feb 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Landau-Kleffner syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000638225.3
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
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) … (more)
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). (less)
|
|
|
Pathogenic
(Jan 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329757.6
First in ClinVar: Dec 06, 2016 Last updated: Feb 07, 2023 |
Comment:
Reported previously in a family with verbal dyspraxia, atypical Rolandic epilepsy, and continuous spike and wave during slow-wave sleep syndrome, and in an individual with … (more)
Reported previously in a family with verbal dyspraxia, atypical Rolandic epilepsy, and continuous spike and wave during slow-wave sleep syndrome, and in an individual with Landau-Kleffner syndrome (Lesca et al., 2013; Conroy et al., 2014); Published functional studies show that the R518H variant impacts NMDA receptor function (Lesca et al., 2013; Sibarov et al., 2017)); 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: 24828792, no PMID, 23933820, 27839871, 28611597, 27683935, 30544257, 33240831, 32102377, 32144935, 29976148, 33823469, 32877683, Elmasri2020[article]) (less)
|
|
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Pathogenic
(Sep 01, 2013)
|
no assertion criteria provided
Method: literature only
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EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000106001.3
First in ClinVar: Nov 21, 2013 Last updated: Oct 21, 2018 |
Comment on evidence:
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 … (more)
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. (less)
|
|
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not provided
(-)
|
no classification provided
Method: literature only
|
Landau-Kleffner syndrome
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000320741.2
First in ClinVar: Oct 11, 2015 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
Reported previously in a family with verbal dyspraxia, atypical Rolandic epilepsy, and continuous spike and wave during slow-wave sleep syndrome, and in an individual with Landau-Kleffner syndrome (Lesca et al., 2013; Conroy et al., 2014); Published functional studies show that the R518H variant impacts NMDA receptor function (Lesca et al., 2013; Sibarov et al., 2017)); 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: 24828792, no PMID, 23933820, 27839871, 28611597, 27683935, 30544257, 33240831, 32102377, 32144935, 29976148, 33823469, 32877683, Elmasri2020[article])
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
loss_of_function_variant
|
|
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002026437.1
|
|
Comment:
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).
Comment:
Reported previously in a family with verbal dyspraxia, atypical Rolandic epilepsy, and continuous spike and wave during slow-wave sleep syndrome, and in an individual with Landau-Kleffner syndrome (Lesca et al., 2013; Conroy et al., 2014); Published functional studies show that the R518H variant impacts NMDA receptor function (Lesca et al., 2013; Sibarov et al., 2017)); 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: 24828792, no PMID, 23933820, 27839871, 28611597, 27683935, 30544257, 33240831, 32102377, 32144935, 29976148, 33823469, 32877683, Elmasri2020[article])
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| GRIN2A-Related Disorders. | Adam MP | - | 2024 | PMID: 27683935 |
| GRIN2A-related disorders: genotype and functional consequence predict phenotype. | Strehlow V | Brain : a journal of neurology | 2019 | PMID: 30544257 |
| Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains. | Swanger SA | American journal of human genetics | 2016 | PMID: 27839871 |
| Towards the identification of a genetic basis for Landau-Kleffner syndrome. | Conroy J | Epilepsia | 2014 | PMID: 24828792 |
| GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. | Lesca G | Nature genetics | 2013 | PMID: 23933820 |
Text-mined citations for rs397518470 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 03, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.