Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function, dominant negative and gain of function are known mechanisms of disease in this gene and are associated with focal epilepsy with speech disorder and with or without mental retardation (MIM#245570). Haploinsufficiency of GRIN2A is known to result in disease, and some variants have also been shown to act antagonistically to the wild type allele when two homologous subunits are incorporated into the same protein complex. Furthermore, the overall effect of these variants on complex activity results in a gain of function of the NMDA receptor (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Some carriers of familial variants are unaffected (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Disease presentation and severity is known to vary, even amongst family members carrying the same variant (OMIM). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0704 - Another canonical splice site variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternate change to thymine at the same nucleotide has previously been reported in individuals with epilepsy (ClinVar, PMID: 23933819). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in more the five unrelated individuals with variable phenotypes on the epilepsy-aphasia spectrum (ClinVar, PMID: 23933819, PMID: 29124671). (SP) 0901 - This variant has strong evidence for segregation with disease. The variant has previously been shown to segregate with disease in at least two families (PMID: 23933819). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
ClinVar Genomic variation as it relates to human health
NM_001134407.3(GRIN2A):c.1007+1G>A
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
7 out of 11 submissions contributed to this 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.
11
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001134407.3(GRIN2A):c.1007+1G>A
Variation ID: 88727 Accession: VCV000088727.50
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p13.2 16: 9937958 (GRCh38) [ NCBI UCSC ] 16: 10031815 (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 Apr 20, 2025 Jan 26, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001134407.3:c.1007+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_000833.5:c.1007+1G>A splice donor NM_001134407.2:c.1007+1G>A NM_001134408.2:c.1007+1G>A splice donor NC_000016.10:g.9937958C>T NC_000016.9:g.10031815C>T NG_011812.2:g.249797G>A - Protein change
- -
- Other names
-
IVS4DS, G-A, +1
- Canonical SPDI
- NC_000016.10:9937957:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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 |
2276 | 2329 | |
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 (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 26, 2025 | RCV000074386.45 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jan 1, 2017 | RCV000656049.2 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 22, 2024 | RCV000726036.34 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV002274908.2 |
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
(May 06, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Landau-Kleffner syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767349.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function, dominant negative and gain … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function, dominant negative and gain of function are known mechanisms of disease in this gene and are associated with focal epilepsy with speech disorder and with or without mental retardation (MIM#245570). Haploinsufficiency of GRIN2A is known to result in disease, and some variants have also been shown to act antagonistically to the wild type allele when two homologous subunits are incorporated into the same protein complex. Furthermore, the overall effect of these variants on complex activity results in a gain of function of the NMDA receptor (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Some carriers of familial variants are unaffected (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Disease presentation and severity is known to vary, even amongst family members carrying the same variant (OMIM). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0704 - Another canonical splice site variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternate change to thymine at the same nucleotide has previously been reported in individuals with epilepsy (ClinVar, PMID: 23933819). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in more the five unrelated individuals with variable phenotypes on the epilepsy-aphasia spectrum (ClinVar, PMID: 23933819, PMID: 29124671). (SP) 0901 - This variant has strong evidence for segregation with disease. The variant has previously been shown to segregate with disease in at least two families (PMID: 23933819). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(Nov 22, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002043969.4
First in ClinVar: Jan 01, 2022 Last updated: Nov 30, 2024 |
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; … (more)
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28102150, 23933818, 7574460, 28832001, 29358611, 25921602, 31873310, 29124671, 30544257, 27683935, 16199547, 31440721, 23933820, 23933819, 37393044, 38715655, 38388889) (less)
|
|
|
Pathogenic
(Dec 01, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249506.29
First in ClinVar: May 12, 2020 Last updated: Apr 20, 2025 |
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Jan 01, 2019)
C
Contributing to aggregate classification
|
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: SCV002026172.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
|
|
|
Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Landau-Kleffner syndrome
Affected status: yes
Allele origin:
germline
|
Juno Genomics, Hangzhou Juno Genomics, Inc
Accession: SCV005418560.1
First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024 |
Comment:
PM2_Supporting+PVS1+PS4_Moderate+PS2_Supporting
|
|
|
Pathogenic
(Jan 26, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Landau-Kleffner syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000761171.9
First in ClinVar: Aug 14, 2017 Last updated: Feb 25, 2025 |
Comment:
This sequence change affects a donor splice site in intron 4 of the GRIN2A gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 4 of the GRIN2A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GRIN2A are known to be pathogenic (PMID: 23933819, 23933820). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Landau-Kleffner syndrome, atypical benign partial epilepsy, benign epilepsy with centrotemporal spikes, and focal epilepsy (PMID: 23933818, 23933819, 28102150). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 88727). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jun 03, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000341369.5
First in ClinVar: Dec 06, 2016 Last updated: Apr 13, 2025 |
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: mixed
|
|
|
Pathogenic
(Jan 01, 2017)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: case-control
|
Self-limited epilepsy with centrotemporal spikes
Affected status: yes
Allele origin:
germline
|
Bioinformatics Core, Luxembourg Center for Systems Biomedicine
Study: EUROEPINOMICS COGIE
Accession: SCV000588325.1 First in ClinVar: Jun 01, 2018 Last updated: Jun 01, 2018 |
Comment:
CAADphred>15
|
|
|
Pathogenic
(Sep 01, 2013)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: literature only
|
EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000105996.3
First in ClinVar: Nov 21, 2013 Last updated: Oct 21, 2018 |
Comment on evidence:
In affected members of a family with autosomal dominant rolandic epilepsy, mental retardation, and speech dyspraxia (FESD; 245570), originally reported by Scheffer et al. (1995), … (more)
In affected members of a family with autosomal dominant rolandic epilepsy, mental retardation, and speech dyspraxia (FESD; 245570), originally reported by Scheffer et al. (1995), Carvill et al. (2013) identified a heterozygous G-to-A transition in intron 4 of the GRIN2A gene (c.1007+1G-A), predicted to result in the skipping of exon 4 and premature termination (Phe139IlefsTer15). The mutation was not found in 6,500 control exomes. The same heterozygous mutation was also found in a father and son with epileptic encephalopathy with continuous spike and wave in slow-wave sleep. Analysis of patient cells showed that the mutant transcript underwent nonsense-mediate mRNA decay. Both of the families were of European descent, and haplotype analysis indicated a founder effect. The findings suggested that GRIN2A mutations can cause a spectrum of epilepsy-aphasia phenotypes. Lemke et al. (2013) identified a heterozygous c.1007+1G-A in 7 affected individuals from 3 unrelated families and in a singleton individual, all with variable manifestations of epilepsy, including Landau-Kleffner syndrome, continuous spike and waves during slow-wave sleep, atypical benign partial epilepsy, and benign epilepsy with centrotemporal spikes. Lemke et al. (2013) suggested that additional modifying factors might explain the phenotypic variability. (less)
|
|
|
Likely pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Abnormal cerebral morphology
Affected status: yes
Allele origin:
de novo
|
Diagnostic Laboratory, Strasbourg University Hospital
Accession: SCV002562802.1
First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022 |
Zygosity: Single Heterozygote
|
|
|
not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
Method: literature only
|
Landau-Kleffner syndrome
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000320740.2
First in ClinVar: Oct 11, 2015 Last updated: Oct 01, 2022 |
|
|
| click to load more submissions click to collapse | |||||
Comment:
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28102150, 23933818, 7574460, 28832001, 29358611, 25921602, 31873310, 29124671, 30544257, 27683935, 16199547, 31440721, 23933820, 23933819, 37393044, 38715655, 38388889)
Comment:
PM2_Supporting+PVS1+PS4_Moderate+PS2_Supporting
Comment:
This sequence change affects a donor splice site in intron 4 of the GRIN2A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GRIN2A are known to be pathogenic (PMID: 23933819, 23933820). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Landau-Kleffner syndrome, atypical benign partial epilepsy, benign epilepsy with centrotemporal spikes, and focal epilepsy (PMID: 23933818, 23933819, 28102150). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 88727). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
CAADphred>15
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function, dominant negative and gain of function are known mechanisms of disease in this gene and are associated with focal epilepsy with speech disorder and with or without mental retardation (MIM#245570). Haploinsufficiency of GRIN2A is known to result in disease, and some variants have also been shown to act antagonistically to the wild type allele when two homologous subunits are incorporated into the same protein complex. Furthermore, the overall effect of these variants on complex activity results in a gain of function of the NMDA receptor (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Some carriers of familial variants are unaffected (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Disease presentation and severity is known to vary, even amongst family members carrying the same variant (OMIM). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0704 - Another canonical splice site variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternate change to thymine at the same nucleotide has previously been reported in individuals with epilepsy (ClinVar, PMID: 23933819). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in more the five unrelated individuals with variable phenotypes on the epilepsy-aphasia spectrum (ClinVar, PMID: 23933819, PMID: 29124671). (SP) 0901 - This variant has strong evidence for segregation with disease. The variant has previously been shown to segregate with disease in at least two families (PMID: 23933819). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28102150, 23933818, 7574460, 28832001, 29358611, 25921602, 31873310, 29124671, 30544257, 27683935, 16199547, 31440721, 23933820, 23933819, 37393044, 38715655, 38388889)
Comment:
PM2_Supporting+PVS1+PS4_Moderate+PS2_Supporting
Comment:
This sequence change affects a donor splice site in intron 4 of the GRIN2A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GRIN2A are known to be pathogenic (PMID: 23933819, 23933820). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Landau-Kleffner syndrome, atypical benign partial epilepsy, benign epilepsy with centrotemporal spikes, and focal epilepsy (PMID: 23933818, 23933819, 28102150). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 88727). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
CAADphred>15
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 |
| Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy. | Bobbili DR | European journal of human genetics : EJHG | 2018 | PMID: 29358611 |
| Mutations of N-Methyl-D-Aspartate Receptor Subunits in Epilepsy. | Xu XX | Neuroscience bulletin | 2018 | PMID: 29124671 |
| Ultra-rare genetic variation in common epilepsies: a case-control sequencing study. | Epi4K consortium | The Lancet. Neurology | 2017 | PMID: 28102150 |
| 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 |
| Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. | Lemke JR | Nature genetics | 2013 | PMID: 23933819 |
| GRIN2A mutations cause epilepsy-aphasia spectrum disorders. | Carvill GL | Nature genetics | 2013 | PMID: 23933818 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| Autosomal dominant rolandic epilepsy and speech dyspraxia: a new syndrome with anticipation. | Scheffer IE | Annals of neurology | 1995 | PMID: 7574460 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GRIN2A | - | - | - | - |
| click to load more citations click to collapse | ||||
Text-mined citations for rs397518465 ...
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 Apr 20, 2025
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.