Human Gene Module / Chromosome 11 / GRM5

GRM5glutamate metabotropic receptor 5

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
9 / 12
Rare Variants / Common Variants
25 / 1
Aliases
GRM5, GPRC1E,  MGLUR5,  mGlu5
Associated Syndromes
-
Chromosome Band
11q14.2-q14.3
Associated Disorders
-
Relevance to Autism

A de novo in-frame deletion variant in the GRM5 gene was identified by exome sequencing in an ASD case from the Simons Simplex Collection (Iossifov et al., 2012). Twelve rare variants in the GRM5 gene were identified in a cohort of 290 non-syndromic ASD cases that were not observed in 300 ethnically matched controls in a subsequent study (Kelleher III et al., 2012).

Molecular Function

Receptor for glutamate. The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system and generates a calcium-activated chloride current

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome Informatics
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to GRM5 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy Klassen T , et al. (2011) No -
2 Positive Association Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder Elia J , et al. (2011) No -
3 Primary De novo gene disruptions in children on the autistic spectrum Iossifov I , et al. (2012) Yes -
4 Support High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism Kelleher RJ 3rd , et al. (2012) Yes -
5 Recent Recommendation Decreased expression of mGluR5 within the dorsolateral prefrontal cortex in autism and increased microglial number in mGluR5 knockout mice: Pathophysiological and neurobehavioral implications Chana G , et al. (2015) Yes -
6 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
7 Recent Recommendation Shank Proteins Couple the Endocytic Zone to the Postsynaptic Density to Control Trafficking and Signaling of Metabotropic Glutamate Receptor 5 Scheefhals N , et al. (2019) No -
8 Support - Xu J et al. (2021) Yes -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Eshraghi AA et al. (2022) Yes -
11 Support - Sheth F et al. (2023) Yes DD, ID
12 Support - Hosneara Akter et al. () Yes -
Rare Variants   (25)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.911+3G>A - intron_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.2630+10G>A - intron_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.1361T>C p.Ile454Thr missense_variant Unknown - - 39342494 Hosneara Akter et al. ()
c.181C>T p.Arg61Cys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.523A>G p.Thr175Ala missense_variant De novo - Simplex 30504930 Guo H , et al. (2018)
c.5T>C p.Val2Ala missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.577C>T p.Pro193Ser missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.2652G>A p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.87T>C p.Ala29= synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.412C>T p.Arg138Cys missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.381A>G p.Val127= synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.657A>C p.Thr219= synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1358C>T p.Thr453Met missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1949G>A p.Gly650Asp missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1206C>T p.Asn402= synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.727G>T p.Ala243Ser missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.846G>A p.Thr282= synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.1417G>C p.Glu473Gln missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.1167A>G p.Thr389= synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.2127T>A p.Val709= synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.2379T>C p.Phe793= synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.3503T>C p.Leu1168Pro missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.3027G>A p.Ser1009= synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.2702A>G p.Asn901Ser missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
c.2036_2038del p.Lys679del inframe_deletion De novo - Simplex 22542183 Iossifov I , et al. (2012)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - copy_number_loss - - - 22138692 Elia J , et al. (2011)
SFARI Gene score
2

Strong Candidate

A de novo in-frame deletion variant in the GRM5 gene was identified by exome sequencing in an ASD case from the Simons Simplex Collection (Iossifov et al., 2012). Twelve rare variants in the GRM5 gene were identified in a cohort of 290 non-syndromic ASD cases that were not observed in 300 ethnically matched controls in a subsequent study (Kelleher III et al., 2012). Deletions with an overlapping region within an intron of the GRM5 gene were found to be statistically enriched in ADHD cases compared to controls (ten cases vs. one control, P = 1.36E-06) in Elia et al., 2011.

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

A de novo in-frame deletion variant in the GRM5 gene was identified by exome sequencing in an ASD case from the Simons Simplex Collection (Iossifov et al., 2012). Twelve rare variants in the GRM5 gene were identified in a cohort of 290 non-syndromic ASD cases that were not observed in 300 ethnically matched controls in a subsequent study (Kelleher III et al., 2012). Deletions with an overlapping region within an intron of the GRM5 gene were found to be statistically enriched in ADHD cases compared to controls (ten cases vs. one control, P = 1.36E-06) in Elia et al., 2011.

4/1/2021
3
icon
3

Decreased from 3 to 3

Description

A de novo in-frame deletion variant in the GRM5 gene was identified by exome sequencing in an ASD case from the Simons Simplex Collection (Iossifov et al., 2012). Twelve rare variants in the GRM5 gene were identified in a cohort of 290 non-syndromic ASD cases that were not observed in 300 ethnically matched controls in a subsequent study (Kelleher III et al., 2012). Deletions with an overlapping region within an intron of the GRM5 gene were found to be statistically enriched in ADHD cases compared to controls (ten cases vs. one control, P = 1.36E-06) in Elia et al., 2011.

Reports Added
[Genetic disruption of Grm5 causes complex alterations in motor activity, anxiety and social behaviors2021]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A de novo in-frame deletion variant in the GRM5 gene was identified by exome sequencing in an ASD case from the Simons Simplex Collection (Iossifov et al., 2012). Twelve rare variants in the GRM5 gene were identified in a cohort of 290 non-syndromic ASD cases that were not observed in 300 ethnically matched controls in a subsequent study (Kelleher III et al., 2012). Deletions with an overlapping region within an intron of the GRM5 gene were found to be statistically enriched in ADHD cases compared to controls (ten cases vs. one control, P = 1.36E-06) in Elia et al., 2011.

Reports Added
[Shank Proteins Couple the Endocytic Zone to the Postsynaptic Density to Control Trafficking and Signaling of Metabotropic Glutamate Receptor 5.2019] [New Scoring Scheme]
10/1/2018
4
icon
4

Decreased from 4 to 4

Description

A de novo in-frame deletion variant in the GRM5 gene was identified by exome sequencing in an ASD case from the Simons Simplex Collection (Iossifov et al., 2012). Twelve rare variants in the GRM5 gene were identified in a cohort of 290 non-syndromic ASD cases that were not observed in 300 ethnically matched controls in a subsequent study (Kelleher III et al., 2012). Deletions with an overlapping region within an intron of the GRM5 gene were found to be statistically enriched in ADHD cases compared to controls (ten cases vs. one control, P = 1.36E-06) in Elia et al., 2011.

Reports Added
[Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
7/1/2018
icon
4

Increased from to 4

Description

A de novo in-frame deletion variant in the GRM5 gene was identified by exome sequencing in an ASD case from the Simons Simplex Collection (Iossifov et al., 2012). Twelve rare variants in the GRM5 gene were identified in a cohort of 290 non-syndromic ASD cases that were not observed in 300 ethnically matched controls in a subsequent study (Kelleher III et al., 2012). Deletions with an overlapping region within an intron of the GRM5 gene were found to be statistically enriched in ADHD cases compared to controls (ten cases vs. one control, P = 1.36E-06) in Elia et al., 2011.

Krishnan Probability Score

Score 0.61158841655465

Ranking 196/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.98598406827088

Ranking 1957/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.94706996667257

Ranking 17126/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 33

Ranking 65/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.32974963953557

Ranking 2295/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
GPRASP1 G protein-coupled receptor associated sorting protein 1 Human Protein Binding 9737 Q5JY77
Rgs4 regulator of G-protein signaling 4 Rat Protein Binding 29480 P49799
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