Published functional studies demonstrate that G820A stabilizes long-lived open states leading to slow deactivation and high Ca2+ permeability (Amin et al., 2018); This variant is associated with the following publications: (PMID: 28867141, 27818011, 28135719, 28856709, 28377535, 29681796, 30217972, 28191890, 33490948, 32144935, 33176815)
ClinVar Genomic variation as it relates to human health
NM_000834.5(GRIN2B):c.2459G>C (p.Gly820Ala)
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.
(11)
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
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000834.5(GRIN2B):c.2459G>C (p.Gly820Ala)
Variation ID: 208643 Accession: VCV000208643.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12p13.1 12: 13567164 (GRCh38) [ NCBI UCSC ] 12: 13720098 (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 Sep 14, 2015 Feb 28, 2024 Mar 13, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000834.5:c.2459G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000825.2:p.Gly820Ala missense NC_000012.12:g.13567164C>G NC_000012.11:g.13720098C>G NG_031854.2:g.419849G>C - Protein change
- G820A
- Other names
- -
- Canonical SPDI
- NC_000012.12:13567163:C:G
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
- 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. |
|||
| GRIN2B | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1540 | 1583 | |
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 (1) |
criteria provided, single submitter
|
Jan 18, 2019 | RCV000190648.3 | |
| Pathogenic (4) |
criteria provided, single submitter
|
Apr 1, 2021 | RCV000235569.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 13, 2023 | RCV000464558.9 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 21, 2023 | RCV000791283.5 | |
| Pathogenic (1) |
no assertion criteria provided
|
Oct 22, 2018 | RCV001265246.1 |
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
(Apr 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000293376.8
First in ClinVar: Jul 24, 2016 Last updated: Apr 17, 2019 |
Comment:
Published functional studies demonstrate that G820A stabilizes long-lived open states leading to slow deactivation and high Ca2+ permeability (Amin et al., 2018); This variant is … (more)
Published functional studies demonstrate that G820A stabilizes long-lived open states leading to slow deactivation and high Ca2+ permeability (Amin et al., 2018); This variant is associated with the following publications: (PMID: 28867141, 27818011, 28135719, 28856709, 28377535, 29681796, 30217972, 28191890, 33490948, 32144935, 33176815) (less)
|
|
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Pathogenic
(Jan 18, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000244088.6
First in ClinVar: Sep 14, 2015 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Muscular hypotonia (present) , Global developmental delay (present) , Absent speech (present) , Myoclonus (present)
Sex: female
Ethnicity/Population group: Hispanic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Failure to thrive (present) , Brisk reflexes (present) , Laryngomalacia (present) , Hypermetropia (present) , Dysphagia (present) , Muscular hypotonia (present) , Neurodevelopmental delay (present) … (more)
Failure to thrive (present) , Brisk reflexes (present) , Laryngomalacia (present) , Hypermetropia (present) , Dysphagia (present) , Muscular hypotonia (present) , Neurodevelopmental delay (present) , Gastroesophageal reflux (present) , Abnormality of the subarachnoid space (present) (less)
Sex: male
Ethnicity/Population group: Caucasian
|
|
|
Pathogenic
(Mar 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 27
Intellectual disability, autosomal dominant 6
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000552119.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly820 amino acid residue in GRIN2B. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly820 amino acid residue in GRIN2B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25356899). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 GRIN2B protein function. ClinVar contains an entry for this variant (Variation ID: 208643). This missense change has been observed in individual(s) with clinical features of epileptic encephalopathy and developmental delay (PMID: 28856709; Invitae). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs797044849, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 820 of the GRIN2B protein (p.Gly820Ala). (less)
|
|
|
Likely pathogenic
(Feb 08, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability, autosomal dominant 6
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV000930581.1 First in ClinVar: Aug 04, 2019 Last updated: Aug 04, 2019 |
Number of individuals with the variant: 1
Clinical Features:
Urinary incontinence (present) , Synophrys (present) , Severe global developmental delay (present) , Scoliosis (present) , Overlapping toe (present) , Knee flexion contracture (present) , … (more)
Urinary incontinence (present) , Synophrys (present) , Severe global developmental delay (present) , Scoliosis (present) , Overlapping toe (present) , Knee flexion contracture (present) , Generalized hypotonia (present) , Gastroesophageal reflux (present) , Failure to thrive in infancy (present) , Dysphagia (present) , Deeply set eye (present) , Coxa valga (present) , Constipation (present) , Cognitive impairment (present) , Cortical visual impairment (present) , Autistic disorder of childhood onset (present) (less)
Age: 10-19 years
Sex: female
Ethnicity/Population group: White
Testing laboratory: HudsonAlpha
Date variant was reported to submitter: 2018-06-26
Testing laboratory interpretation: Uncertain significance
|
|
|
Likely pathogenic
(Apr 04, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability, autosomal dominant 6
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001335375.1
First in ClinVar: Jun 11, 2020 Last updated: Jun 11, 2020 |
Comment:
This variant was identified as de novo (maternity and paternity confirmed).
|
|
|
Pathogenic
(Oct 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability, autosomal dominant 6
Affected status: yes
Allele origin:
unknown
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976966.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PS2, PM1, PM2, PM5, PP2, PP3
|
|
|
Pathogenic
(Feb 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability, autosomal dominant 6
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV003932141.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Comment:
PS3_Moderate, PM2, PM6_Strong, PP2, PP3
|
|
|
Pathogenic
(Oct 22, 2018)
|
no assertion criteria provided
Method: provider interpretation
|
Complex neurodevelopmental disorder
Affected status: yes
Allele origin:
de novo
|
GenomeConnect - Simons Searchlight
Accession: SCV001443360.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-10-22 and interpreted as Pathogenic. The reporting laboratory … (more)
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-10-22 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. (less)
Observation 1:
Number of individuals with the variant: 1
Sex: male
Testing laboratory: Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center
Date variant was reported to submitter: 2014-03-25
Testing laboratory interpretation: Likely pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Oligohydramnios (present) , Poor suck (present) , Feeding difficulties in infancy (present) , Abnormality of vision (present) , Strabismus (present) , Ptosis (present) , Cortical … (more)
Oligohydramnios (present) , Poor suck (present) , Feeding difficulties in infancy (present) , Abnormality of vision (present) , Strabismus (present) , Ptosis (present) , Cortical visual impairment (present) , Generalized hypotonia (present) , Hypertonia (present) , Cerebral palsy (present) , Seizures (present) , Focal seizures with impairment of consciousness or awareness (present) , Gastroesophageal reflux (present) , Constipation (present) , Otitis media (present) , Pneumonia (present) , Abnormality of the respiratory system (present) , Pneumonia (present) , Abnormality of the urinary system (present) , Abnormality of the skin (present) , Eczema (present) (less)
Age: 10-19 years
Sex: male
Testing laboratory: Genome Diagnostics Laboratory,University Medical Center Utrecht
Date variant was reported to submitter: 2013-07-08
Testing laboratory interpretation: Likely pathogenic
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Neonatal hypotonia (present) , Feeding difficulties in infancy (present) , Strabismus (present) , Generalized hypotonia (present) , Gastroesophageal reflux (present) , Pneumonia (present) , Abnormality … (more)
Neonatal hypotonia (present) , Feeding difficulties in infancy (present) , Strabismus (present) , Generalized hypotonia (present) , Gastroesophageal reflux (present) , Pneumonia (present) , Abnormality of the respiratory system (present) , Recurrent respiratory infections (present) , Failure to thrive (present) (less)
Age: 0-9 years
Sex: male
Testing laboratory: South West Thames Regional Genetics Service, NHS
Date variant was reported to submitter: 2015-01-16
Testing laboratory interpretation: Pathogenic
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931004.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001959693.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001963223.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
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Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly820 amino acid residue in GRIN2B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25356899). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 GRIN2B protein function. ClinVar contains an entry for this variant (Variation ID: 208643). This missense change has been observed in individual(s) with clinical features of epileptic encephalopathy and developmental delay (PMID: 28856709; Invitae). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs797044849, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 820 of the GRIN2B protein (p.Gly820Ala).
Comment:
This variant was identified as de novo (maternity and paternity confirmed).
Comment:
PS2, PM1, PM2, PM5, PP2, PP3
Comment:
PS3_Moderate, PM2, PM6_Strong, PP2, PP3
Comment:
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-10-22 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight.
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:
Published functional studies demonstrate that G820A stabilizes long-lived open states leading to slow deactivation and high Ca2+ permeability (Amin et al., 2018); This variant is associated with the following publications: (PMID: 28867141, 27818011, 28135719, 28856709, 28377535, 29681796, 30217972, 28191890, 33490948, 32144935, 33176815)
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly820 amino acid residue in GRIN2B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25356899). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 GRIN2B protein function. ClinVar contains an entry for this variant (Variation ID: 208643). This missense change has been observed in individual(s) with clinical features of epileptic encephalopathy and developmental delay (PMID: 28856709; Invitae). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs797044849, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 820 of the GRIN2B protein (p.Gly820Ala).
Comment:
This variant was identified as de novo (maternity and paternity confirmed).
Comment:
PS2, PM1, PM2, PM5, PP2, PP3
Comment:
PS3_Moderate, PM2, PM6_Strong, PP2, PP3
Comment:
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-10-22 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. | Marinakis NM | American journal of medical genetics. Part A | 2021 | PMID: 34008892 |
| A conserved glycine harboring disease-associated mutations permits NMDA receptor slow deactivation and high Ca(2+) permeability. | Amin JB | Nature communications | 2018 | PMID: 30217972 |
| GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy. | Yoo Y | Annals of neurology | 2017 | PMID: 28856709 |
| GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects. | Platzer K | Journal of medical genetics | 2017 | PMID: 28377535 |
| Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples. | Kosmicki JA | Nature genetics | 2017 | PMID: 28191890 |
| De novo mutations in moderate or severe intellectual disability. | Hamdan FF | PLoS genetics | 2014 | PMID: 25356899 |
| GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy. | Lemke JR | Annals of neurology | 2014 | PMID: 24272827 |
Text-mined citations for rs797044849 ...
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 Sep 29, 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.