Human Gene Module / Chromosome 7 / RHEB

RHEBRas homolog, mTORC1 binding

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
1 / 3
Rare Variants / Common Variants
3 / 0
Aliases
RHEB, RHEB2
Associated Syndromes
-
Chromosome Band
7q36.1
Associated Disorders
EPS
Relevance to Autism

Analysis of 101 mTOR-related genes in a cohort of 826 patients with intellectual disability (ID) identified three individuals from two families with de novo missense variants in the RHEB gene that, in addition to ID, presented with macrocephaly and autism spectrum disorder/autistic features; functional analysis of both RHEB missense variants in animal models revealed increased head size in zebrafish and aberrant neuronal migration and induction of seizures in mice (Reijnders et al., 2017).

Molecular Function

This gene is a member of the small GTPase superfamily and encodes a lipid-anchored, cell membrane protein with five repeats of the RAS-related GTP-binding region. This protein is vital in regulation of growth and cell cycle progression due to its role in the insulin/TOR/S6K signaling pathway. The protein has GTPase activity and shuttles between a GDP-bound form and a GTP-bound form, and farnesylation of the protein is required for this activity.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
Fruit fly
Entrez Gene
Zebrafish
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to RHEB (3 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability Reijnders MRF , et al. (2017) Yes Epilepsy/seizures
2 Support - Spataro N et al. (2023) No -
3 Support - Lena H Nguyen et al. (2024) No -
Rare Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.71T>C p.Ile24Thr missense_variant De novo - Simplex 36980980 Spataro N et al. (2023)
c.202T>C p.Ser68Pro missense_variant De novo - Simplex 29051493 Reijnders MRF , et al. (2017)
c.110C>T p.Pro37Leu missense_variant De novo (germline mosaicism) - Multiplex 29051493 Reijnders MRF , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Analysis of 101 mTOR-related genes in a cohort of 826 patients with intellectual disability (ID) identified three individuals from two families with de novo missense variants in the RHEB gene that, in addition to ID, presented with macrocephaly and autism spectrum disorder/autistic features; functional analysis of both RHEB missense variants in animal models revealed increased head size in zebrafish and aberrant neuronal migration and induction of seizures in mice (Reijnders et al., 2017).

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Analysis of 101 mTOR-related genes in a cohort of 826 patients with intellectual disability (ID) identified three individuals from two families with de novo missense variants in the RHEB gene that, in addition to ID, presented with macrocephaly and autism spectrum disorder/autistic features; functional analysis of both RHEB missense variants in animal models revealed increased head size in zebrafish and aberrant neuronal migration and induction of seizures in mice (Reijnders et al., 2017).

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.49393112295283

Ranking 3911/25841 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 0.95442041345634

Ranking 2611/18225 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 0.90350545984098

Ranking 6745/18665 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
Zhang D Score

Score -0.013487137927939

Ranking 9109/20870 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
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