Human Gene Module / Chromosome 16 / GRIN2A

GRIN2Aglutamate receptor, ionotropic, N-methyl D-aspartate 2A

Score
4
Minimal Evidence Criteria 4.1
Autism Reports / Total Reports
5 / 30
Rare Variants / Common Variants
85 / 4
Aliases
GRIN2A, NR2A,  NMDAR2A
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Chromosome Band
16p13.2
Associated Disorders
ASD, DD/NDD, EPS, ADHD, ID, EP
Relevance to Autism

Genetic association has been found between the GRIN2A gene and autism in an IMGSAC cohort (Barnby et al., 2005).

Molecular Function

The encoded protein is a subunit of N-methyl-D-aspartate (NMDA) selective glutamate receptors.

Reports related to GRIN2A (30 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT. Barnby G , et al. (2005) Yes -
2 Recent Recommendation Integrative properties of radial oblique dendrites in hippocampal CA1 pyramidal neurons. Losonczy A and Magee JC (2006) No -
3 Recent Recommendation Cholesterol-enriched diet affects spatial learning and synaptic function in hippocampal synapses. Dufour F , et al. (2006) No -
4 Recent Recommendation Zinc modulates bidirectional hippocampal plasticity by effects on NMDA receptors. Izumi Y , et al. (2006) No -
5 Recent Recommendation NMDA receptor function: subunit composition versus spatial distribution. Khr G (2006) No -
6 Support Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Endele S , et al. (2010) No ID
7 Support Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Klassen T , et al. (2011) No -
8 Support Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link wi... Lesca G , et al. (2012) No ADHD
9 Support Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia. Tarabeux J , et al. (2011) Yes -
10 Support Diagnostic exome sequencing in persons with severe intellectual disability. de Ligt J , et al. (2012) No Epilepsy, ASD
11 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Girirajan S , et al. (2013) Yes -
12 Positive association Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Cross-Disorder Group of the Psychiatric Genomics Consortium (2013) Yes -
13 Recent Recommendation GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Carvill GL , et al. (2013) No -
14 Recent Recommendation Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Lemke JR , et al. (2013) No DD, ID
15 Recent Recommendation GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Lesca G , et al. (2013) No -
16 Support Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities. Zhang Y , et al. (2015) No -
17 Support Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms. D'Gama AM , et al. (2015) Yes -
18 Recent recommendation Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease. Johnson MR , et al. (2015) No -
19 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
20 Recent recommendation Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains. Swanger SA , et al. (2016) No ASD (1 case), epilepsy/seizures (1 case)
21 Support Molecular Mechanism of Disease-Associated Mutations in the Pre-M1 Helix of NMDA Receptors and Potential Rescue Pharmacology. Ogden KK , et al. (2017) No -
22 Support Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs. von Stlpnagel C , et al. (2017) No DD, ID
23 Support A de novo loss-of-function GRIN2A mutation associated with childhood focal epilepsy and acquired epileptic aphasia. Gao K , et al. (2017) No -
24 Recent recommendation Epilepsy-associated GRIN2A mutations reduce NMDA receptor trafficking and agonist potency - molecular profiling and functional rescue. Addis L , et al. (2017) No -
25 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Vissers LE , et al. (2017) No -
26 Support Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment. Chen XS , et al. (2017) No -
27 Support Functional assessment of the NMDA receptor variant GluN2A R586K. Marwick KFM , et al. (2017) No -
28 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) No -
29 Highly Cited Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Garthwaite J , et al. (1988) No -
30 Highly Cited Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Monyer H , et al. (1994) No -
Rare Variants   (85)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation Familial Maternal & paternal Multi-generational 20890276 Endele S , et al. (2010)
c.652C>T p.Gln218Ter stop_gained Familial Maternal Multi-generational 20890276 Endele S , et al. (2010)
c.1845C>A p.Asn615Lys missense_variant De novo - - 20890276 Endele S , et al. (2010)
c.1757G>A p.Arg586Lys missense_variant Familial Maternal - 20890276 Endele S , et al. (2010)
c.3190A>G p.Thr1064Ala missense_variant - - - 20890276 Endele S , et al. (2010)
c.3228C>G p.Asn1076Lys missense_variant Unknown - - 20890276 Endele S , et al. (2010)
C>T p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
G>T p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2332G>C p.Ala778Pro missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
C>T p.Met788Ile missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2855A>G p.Lys952Arg missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
- - copy_number_loss De novo - Unknown 22738016 Lesca G , et al. (2012)
c.2902G>A p.Ala968Thr missense_variant De novo - Simplex 22833210 Tarabeux J , et al. (2011)
c.3669C>T p.(=) synonymous_variant De novo - Simplex 22833210 Tarabeux J , et al. (2011)
c.428C>T p.Thr143Ile missense_variant - - - 22833210 Tarabeux J , et al. (2011)
c.2765C>T p.Ala922Val missense_variant - - - 22833210 Tarabeux J , et al. (2011)
c.1945C>G p.Leu649Val missense_variant De novo - - 23033978 de Ligt J , et al. (2012)
c.1655C>G p.Pro552Arg missense_variant De novo - - 23033978 de Ligt J , et al. (2012)
- - copy_number_gain Familial Maternal Multiplex 23375656 Girirajan S , et al. (2013)
c.1007 + 1G>A p.Phe139IlefsTer15 splice_site_variant Familial Family A: maternal and paternal; family C: paternal Multi-generational 23933818 Carvill GL , et al. (2013)
c.2T>C p.Met1Thr initiator_codon_variant Familial Paternal Multi-generational 23933818 Carvill GL , et al. (2013)
c.1592C>T p.Thr531Met missense_variant Familial Maternal Multiplex 23933818 Carvill GL , et al. (2013)
c.728C>T p.Ala243Val missense_variant Unknown - Unknown 23933819 Lemke JR , et al. (2013)
c.2041C>T p.Arg681Ter stop_gained Familial Maternal Multi-generational 23933819 Lemke JR , et al. (2013)
c.1007 + 1G>A - splice_site_variant Unknown (n=2), Familial (n=2) Maternal (n=2) Unknown (n=1), multiplex (n=3) 23933819 Lemke JR , et al. (2013)
c.1108C>T p.Arg370Trp missense_variant Unknown - Unknown 23933819 Lemke JR , et al. (2013)
c.2140G>A p.Glu714Lys missense_variant Unknown - Unknown 23933819 Lemke JR , et al. (2013)
c.2927A>G p.Asn976Ser missense_variant Unknown (both cases) - Unknown (both cases) 23933819 Lemke JR , et al. (2013)
c.594G>A p.Trp198Ter stop_gained Unknown - Unknown 23933819 Lemke JR , et al. (2013)
c.1001T>A p.Leu334Ter stop_gained Familial Paternal Multi-generational 23933819 Lemke JR , et al. (2013)
c.2334_2338delCTTGC p.Leu779SerfsTer5 frameshift_variant Familial Paternal Simplex 23933819 Lemke JR , et al. (2013)
c.2829C>G p.Tyr943Ter stop_gained Familial Paternal Multi-generational 23933819 Lemke JR , et al. (2013)
c.2007 + 1G>A - splice_site_variant Familial Paternal Multi-generational 23933819 Lemke JR , et al. (2013)
c.236C>G p.Pro79Arg missense_variant Familial Maternal Multi-generational 23933819 Lemke JR , et al. (2013)
c.547T>A p.Phe183Ile missense_variant Familial Paternal Simplex 23933819 Lemke JR , et al. (2013)
c.692G>A p.Cys231Tyr missense_variant Familial Maternal Multiplex 23933819 Lemke JR , et al. (2013)
c.869C>T p.Ala290Val missense_variant Unknown - Unknown 23933819 Lemke JR , et al. (2013)
c.1306T>C p.Cys436Arg missense_variant De novo - Multiplex 23933819 Lemke JR , et al. (2013)
c.2095C>T p.Pro699Ser missense_variant De novo - Simplex 23933819 Lemke JR , et al. (2013)
c.2113A>G p.Met705Val missense_variant Familial Maternal Multiplex 23933819 Lemke JR , et al. (2013)
c.2179G>A p.Ala727Thr missense_variant Unknown - Unknown 23933819 Lemke JR , et al. (2013)
c.2200G>C p.Val734Leu missense_variant Familial Paternal Multiplex 23933819 Lemke JR , et al. (2013)
c.2314A>G p.Lys772Glu missense_variant Unknown - Unknown 23933819 Lemke JR , et al. (2013)
c.2441T>C p.Ile814Thr missense_variant Familial Paternal Simplex 23933819 Lemke JR , et al. (2013)
c.2710A>T p.Ile904Phe missense_variant Familial Paternal Multi-generational 23933819 Lemke JR , et al. (2013)
c.90delTins(T)2 p.Pro31SerfsTer107 frameshift_variant Familial Maternal Multi-generational 23933819 Lemke JR , et al. (2013)
c.1585delG p.Val529TrpfsTer22 frameshift_variant Familial Maternal Multi-generational 23933819 Lemke JR , et al. (2013)
c.1637_1639delCTT p.Ser547del inframe_deletion Unknown Not maternal Multiplex 23933819 Lemke JR , et al. (2013)
- - copy_number_loss Unknown - Unknown 23933819 Lemke JR , et al. (2013)
- - copy_number_loss Unknown - Unknown 23933819 Lemke JR , et al. (2013)
- - copy_number_loss Unknown - Unknown 23933819 Lemke JR , et al. (2013)
- - copy_number_gain Unknown - Unknown 23933819 Lemke JR , et al. (2013)
c.1123-2A>G p.Val375fs splice_site_variant Familial Maternal Multi-generational 23933820 Lesca G , et al. (2013)
- - copy_number_loss Familial Maternal Multiplex 23933820 Lesca G , et al. (2013)
- Phe670fs copy_number_loss Familial Maternal Multi-generational 23933820 Lesca G , et al. (2013)
c.4161C>A p.Tyr1387Ter stop_gained Familial Maternal Multi-generational 23933820 Lesca G , et al. (2013)
c.1510C>T p.Arg504Trp missense_variant Familial Maternal Multiplex 23933820 Lesca G , et al. (2013)
c.1447G>A p.Gly483Arg missense_variant Familial Maternal Multiplex 23933820 Lesca G , et al. (2013)
c.1553G>A p.Arg518His missense_variant Familial Paternal Multi-generational 23933820 Lesca G , et al. (2013)
c.2191G>A p.Asp731Asn missense_variant Familial Maternal Multi-generational 23933820 Lesca G , et al. (2013)
c.3751G>A p.Asp1251Asn missense_variant Familial Paternal - 23933820 Lesca G , et al. (2013)
c.2146G>A p.Ala716Thr missense_variant Familial Maternal Multi-generational 23933820 Lesca G , et al. (2013)
c.2797G>A p.Asp933Asn missense_variant Familial Paternal Simplex 23933820 Lesca G , et al. (2013)
c.551T>G p.Ile184Ser missense_variant Familial Maternal Simplex 23933820 Lesca G , et al. (2013)
c.2081T>C p.Ile694Thr missense_variant De novo - Simplex 23933820 Lesca G , et al. (2013)
c.1954T>G p.Phe652Val missense_variant De novo - Simplex 23933820 Lesca G , et al. (2013)
c.1642G>A p.Ala548Thr missense_variant De novo - Simplex 23933820 Lesca G , et al. (2013)
c.2007G>T p.Lys669Asn missense_variant Unknown - Simplex 23933820 Lesca G , et al. (2013)
c.883G>A p.Gly295Ser missense_variant Unknown Not maternal Simplex 23933820 Lesca G , et al. (2013)
c.3827C>G p.Ala1276Gly missense_variant Unknown - Unknown 23933820 Lesca G , et al. (2013)
c.2191G>A p.Asp731Asn missense_variant De novo - Simplex 26544041 Zhang Y , et al. (2015)
c.2650G>A p.Asp884Asn missense_variant Unknown - Unknown 26637798 D'Gama AM , et al. (2015)
c.2450T>C p.Met817Thr missense_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.2054T>C p.Val685Gly missense_variant Unknown - - 27839871 Swanger SA , et al. (2016)
c.1586delT p.Phe528GlyfsTer22 frameshift_variant Unknown - Multi-generational 28109652 von Stlpnagel C , et al. (2017)
c.1818G>A p.Trp606Ter stop_gained Unknown - - 28109652 von Stlpnagel C , et al. (2017)
c.2407G>T p.Glu803Ter stop_gained De novo - - 28109652 von Stlpnagel C , et al. (2017)
c.2007+1G>A p.? splice_site_variant Familial Paternal - 28109652 von Stlpnagel C , et al. (2017)
- - copy_number_gain Unknown - - 28109652 von Stlpnagel C , et al. (2017)
c.1841A>G p.Asn614Ser missense_variant De novo - - 28109652 von Stlpnagel C , et al. (2017)
c.1936A>G p.Thr646Ala missense_variant De novo - - 28109652 von Stlpnagel C , et al. (2017)
c.2191G>A p.Asp731Asn missense_variant De novo - Simplex 28182669 Gao K , et al. (2017)
c.2450T>C p.Met817Thr missense_variant De novo - - 28333917 Vissers LE , et al. (2017)
c.2063G>C p.Gly688Ala missense_variant De novo - Possible multi-generational 28440294 Chen XS , et al. (2017)
c.4375A>G p.Ser1459Gly missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
Common Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1576T>C p.(=) synonymous_variant - - - 15830322 Barnby G , et al. (2005)
c.2316-35G>C - intron_variant - - - 15830322 Barnby G , et al. (2005)
c.*1212C>T;c.*1418C>T - 3_prime_UTR_variant - - - 15830322 Barnby G , et al. (2005)
c.2168+4735G>T;c.2324+4735G>T;c.1697+4735G>T A/C intron_variant - - - 23453885 Cross-Disorder Group of the Psychiatric Genomics Consortium (2013)
SFARI Gene score
4

Minimal Evidence

There is association and linkage evidence for the GRIN2A gene. For example, genetic association has been found between the GRIN2A gene and autism in an IMGSAC cohort (Barnby et al., 2005).

4

Minimal Evidence

See all Category 4 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as 'acc" in the score cards) could also boost a gene from category 4 to 3.

04-01-2017
4

Initial score established: 4

Description

There is association and linkage evidence for the GRIN2A gene. For example, genetic association has been found between the GRIN2A gene and autism in an IMGSAC cohort (Barnby et al., 2005).

Reports Added
[Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link wi...2012] [Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs.2017] [A de novo loss-of-function GRIN2A mutation associated with childhood focal epilepsy and acquired epileptic aphasia.2017] [A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.2017] [Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.2013] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [Cholesterol-enriched diet affects spatial learning and synaptic function in hippocampal synapses.2006] [Zinc modulates bidirectional hippocampal plasticity by effects on NMDA receptors.2006] [GRIN2A mutations cause epilepsy-aphasia spectrum disorders.2013] [Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.2013] [GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.2013] [Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains.2016] [NMDA receptor function: subunit composition versus spatial distribution.2006] [Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia.2011] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015] [Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease.2015] [Functional assessment of the NMDA receptor variant GluN2A R586K.2017] [Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain.1988] [Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment.2017] [Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.2010] [Epilepsy-associated GRIN2A mutations reduce NMDA receptor trafficking and agonist potency - molecular profiling and functional rescue.2017] [Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.1994] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Molecular Mechanism of Disease-Associated Mutations in the Pre-M1 Helix of NMDA Receptors and Potential Rescue Pharmacology.2017] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.2016] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT.2005] [Integrative properties of radial oblique dendrites in hippocampal CA1 pyramidal neurons.2006]
CNVs associated with GRIN2A(1 CNVs)
16p13.2 31 Deletion-Duplication 48  /  213
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