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Intellectual disability

Gene: RHEB

Red List (low evidence)

RHEB (Ras homolog, mTORC1 binding)
EnsemblGeneIds (GRCh38): ENSG00000106615
EnsemblGeneIds (GRCh37): ENSG00000106615
OMIM: 601293, Gene2Phenotype
RHEB is in 1 panel

3 reviews

Zornitza Stark (Australian Genomics)

Green List (high evidence)

I think you meant for this gene to be Amber: three individuals from two unrelated families reported plus animal model data, borderline Green (we have rated as such).
Created: 10 Mar 2020, 4:54 a.m. | Last Modified: 10 Mar 2020, 4:54 a.m.
Panel Version: 3.3

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Intellectual disability; Macrocephaly

Publications

Variants in this GENE are reported as part of current diagnostic practice

Louise Daugherty (Genomics England Curator)

Red List (low evidence)

Comment on list classification: Changed rating of gene from Amber to Red. This gene was rated as Red in v2.467 and incorrectly automatically promoted to Amber in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Created: 29 Sep 2018, 10:27 p.m.
There is currently no evidence to suggest there is an association of this gene with intellectual disability.
Created: 18 Dec 2017, 3:39 p.m.

Rebecca Foulger (Genomics England curator)

Comment on list classification: Updated rating from Red to Amber: 2 families (3 individuals) reported in 2017 paper (PMID:29051493) with 2 different variants. Added 'watchlist' tag to stay informed about new cases.
Created: 23 Oct 2017, 4:01 p.m.
PMID:29051493 (2017) analysed 101 mMTOR-related genes in a large ID patient cohort and 2 independent population cohorts. They report 3 individuals (including 2 siblings) with heterozygous RHEB variants. The siblings carried the c.110 C > T (p.Pro37Leu) variant, and a sporadic individual carried the c.202 T>C (p.Ser68Pro) allele. All 3 individuals had short stature (−2 to −3 SD) and early brain overgrowth with pronounced macrocephaly during childhood (+2.5/+3 SD). They had severe to profound ID with hypotonia, as well as autism spectrum disorder. 2 of 3 individuals were reported to have epilepsy. In a zebrafish model, overexpression of RHEB produced megalencephaly, supporting a hyperactivating effect. This is supported in mice where loss of RHEB activity does not cause an overt neurological phenotype.
Created: 23 Oct 2017, 3:50 p.m.
Comment on phenotypes: Phenotypes taken from PMID:29051493 (2017).
Created: 23 Oct 2017, 3:47 p.m.
Comment on mode of inheritance: Monoallelic MOI reported in PMID:29051493.
Created: 23 Oct 2017, 3:45 p.m.
Comment on publications: The ID work described in the Genomics of Rare Disease (GRD) 2017 conference by Prof. Brunner is published as PMID:29051493 (2017).
Created: 23 Oct 2017, 2:57 p.m.
RHEB added to ID panel based on talk S15 at GRD17 by Prof. Han Brunner. Brunner's group report a novel intellectual disability gene RHEB that is further associated with megalencephaly. Functional testing in a zebrafish model indicated MTOR pathway hyperactivation with a concomitant increase in cell and head size, consistent with the human phenotype.
Created: 12 Apr 2017, 2:29 p.m.

Mode of inheritance
Unknown

Phenotypes
intellectual disability; megalencephaly

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Other
Phenotypes
  • short stature, macrocephaly, intellectual disability and autism spectrum disorder
Tags
watchlist
OMIM
601293
Clinvar variants
Variants in RHEB
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

29 Sep 2018, Gel status: 1

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: rheb has been classified as Red List (Low Evidence).

29 Sep 2018, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to RHEB.

12 Mar 2018, Gel status: 1

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

5 Jan 2018, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

Expert Review Red was added to RHEB. Panel: Intellectual disability

23 Oct 2017, Gel status: 2

Gene classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

This gene has been classified as Amber List (Moderate Evidence).

23 Oct 2017, Gel status: 0

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for RHEB were set to short stature, macrocephaly, intellectual disability and autism spectrum disorder

23 Oct 2017, Gel status: 0

Set Mode of Inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for RHEB was changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

23 Oct 2017, Gel status: 0

Set Mode of Inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for RHEB was changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

23 Oct 2017, Gel status: 0

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for RHEB were set to macrocephaly and intellectual disability

23 Oct 2017, Gel status: 0

Set publications

Rebecca Foulger (Genomics England curator)

Publications for RHEB were set to 29051493

12 Apr 2017, Gel status: 0

Added New Source

Rebecca Foulger (Genomics England curator)

RHEB was added to Intellectual disabilitypanel. Sources: Other

12 Apr 2017, Gel status: 0

Created

Rebecca Foulger (Genomics England curator)

RHEB was created by rfoulger