For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GRIN2A function (PMID: 23933818, 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: 88730). This missense change has been observed in individual(s) with clinical features of GRIN2A-related conditions (PMID: 23933818, 30544257; Invitae). 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 threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 531 of the GRIN2A protein (p.Thr531Met).
ClinVar Genomic variation as it relates to human health
NM_001134407.3(GRIN2A):c.1592C>T (p.Thr531Met)
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.1592C>T (p.Thr531Met)
Variation ID: 88730 Accession: VCV000088730.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p13.2 16: 9840706 (GRCh38) [ NCBI UCSC ] 16: 9934563 (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 21, 2018 Oct 20, 2024 Apr 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001134407.3:c.1592C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001127879.1:p.Thr531Met missense NM_000833.5:c.1592C>T NP_000824.1:p.Thr531Met missense NM_001134408.2:c.1592C>T NP_001127880.1:p.Thr531Met missense NC_000016.10:g.9840706G>A NC_000016.9:g.9934563G>A NG_011812.2:g.347049C>T Q12879:p.Thr531Met - Protein change
- T531M
- Other names
- -
- Canonical SPDI
- NC_000016.10:9840705:G:A
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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]
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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 (3) |
criteria provided, multiple submitters, no conflicts
|
Jun 26, 2023 | RCV000074389.35 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 1, 2024 | RCV001557828.10 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jun 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Landau-Kleffner syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000953322.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GRIN2A function (PMID: 23933818, 27839871). Advanced … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GRIN2A function (PMID: 23933818, 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: 88730). This missense change has been observed in individual(s) with clinical features of GRIN2A-related conditions (PMID: 23933818, 30544257; Invitae). 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 threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 531 of the GRIN2A protein (p.Thr531Met). (less)
|
|
|
Pathogenic
(Apr 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV005041135.6
First in ClinVar: May 12, 2024 Last updated: Oct 20, 2024 |
Comment:
GRIN2A: PS2, PM2, PS4:Moderate, PP2, PS3:Supporting
Number of individuals with the variant: 2
|
|
|
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: SCV002026438.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
|
|
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Pathogenic
(Aug 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001779664.2
First in ClinVar: Aug 13, 2021 Last updated: Sep 14, 2023 |
Comment:
Identified in a family with epileptic encephalopathy with continuous spike and wave during slow wave sleep and intermediate epilepsy-aphasia disorder (Carvill et al., 2013); Published … (more)
Identified in a family with epileptic encephalopathy with continuous spike and wave during slow wave sleep and intermediate epilepsy-aphasia disorder (Carvill et al., 2013); Published functional studies demonstrate a damaging effect (reduced protein level and lack of macroscopic current responses) (Swanger et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28351718, 25921602, 25904555, 25498981, 30544257, 27839871, 33897753, 29455050, 23933818) (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: SCV000105999.2
First in ClinVar: Nov 21, 2013 Last updated: Oct 21, 2018 |
Comment on evidence:
In 3 sibs with focal epilepsy and speech disorder (FESD; 245570), with the clinical diagnosis of epilepsy-aphasia disorder or continuous spike and waves during slow-wave … (more)
In 3 sibs with focal epilepsy and speech disorder (FESD; 245570), with the clinical diagnosis of epilepsy-aphasia disorder or continuous spike and waves during slow-wave sleep syndrome, Carvill et al. (2013) identified a heterozygous c.1592C-T transition in the GRIN2A gene, resulting in a thr531-to-met (T531M) substitution at a highly conserved residue in the extracellular ligand-binding domain. The mutation was not found in 6,500 control exomes. Coexpression of the mutant protein with wildtype GRIN1 (138249) in COS-7 cells resulted in a shift in NMDA receptor kinetics, with a 4-fold increase in the mean duration of the open state compared to wildtype channels. The patients had onset between ages 6.5 and 11 years of focal dyscognitive or tonic-clonic seizures that remitted in 2 patients by age 11 years. The patients had variably delayed development, mild intellectual disability, and speech/language difficulties. EEG findings were all abnormal and differed slightly, including centrotemporal spikes, high-voltage discharges while awake, and continuous spike-waves during sleep. (less)
|
Comment:
Comment:
GRIN2A: PS2, PM2, PS4:Moderate, PP2, PS3:Supporting
Comment:
Identified in a family with epileptic encephalopathy with continuous spike and wave during slow wave sleep and intermediate epilepsy-aphasia disorder (Carvill et al., 2013); Published functional studies demonstrate a damaging effect (reduced protein level and lack of macroscopic current responses) (Swanger et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28351718, 25921602, 25904555, 25498981, 30544257, 27839871, 33897753, 29455050, 23933818)
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: SCV002026438.1
|
|
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GRIN2A function (PMID: 23933818, 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: 88730). This missense change has been observed in individual(s) with clinical features of GRIN2A-related conditions (PMID: 23933818, 30544257; Invitae). 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 threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 531 of the GRIN2A protein (p.Thr531Met).
Comment:
GRIN2A: PS2, PM2, PS4:Moderate, PP2, PS3:Supporting
Comment:
Identified in a family with epileptic encephalopathy with continuous spike and wave during slow wave sleep and intermediate epilepsy-aphasia disorder (Carvill et al., 2013); Published functional studies demonstrate a damaging effect (reduced protein level and lack of macroscopic current responses) (Swanger et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28351718, 25921602, 25904555, 25498981, 30544257, 27839871, 33897753, 29455050, 23933818)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| GRIN2A mutations cause epilepsy-aphasia spectrum disorders. | Carvill GL | Nature genetics | 2013 | PMID: 23933818 |
Text-mined citations for rs397518468 ...
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 Oct 20, 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.