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Intellectual disability
Gene: RHEB

RHEB (Ras homolog, mTORC1 binding)
EnsemblGeneIds (GRCh38): ENSG00000106615
EnsemblGeneIds (GRCh37): ENSG00000106615
OMIM: 601293, Gene2Phenotype
RHEB is in 3 panels

4 reviews

Arina Puzriakova (Genomics England Curator)

Comment on list classification: Three individuals from two unrelated families reported in PMID:29051493 with severe-profound ID - sufficient evidence to rate this gene Amber (previously erroneously demoted to Red).
Created: 8 Oct 2020, 1:26 p.m. | Last Modified: 8 Oct 2020, 1:26 p.m.

Panel Version: 3.385

Created: 8 Oct 2020, 1:26 p.m.
Last Modified: 8 Oct 2020, 1:26 p.m.
Panel version: 3.385

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

29051493

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

Created: 10 Mar 2020, 4:54 a.m.
Last Modified: 10 Mar 2020, 4:54 a.m.
Panel version: 3.3

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.

Created: 18 Dec 2017, 3:39 p.m.

Panel version: Imported from Intellectual disability update Dec 2017 panel version 0.40

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

Created: 23 Oct 2017, 3:45 p.m.

Panel version: 1.439

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Sources

Expert Review Amber
Victorian Clinical Genetics Services
Other

Phenotypes

short stature, macrocephaly, intellectual disability and autism spectrum disorder

Tags

watchlist

OMIM

601293

Clinvar variants

Variants in RHEB

Penetrance

Complete

Publications

29051493

Panels with this gene

History Filter Activity

8 Oct 2020, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: rheb has been classified as Amber List (Moderate Evidence).

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