Intellectual disability - microarray and sequencing
Gene: RHEB Amber List (moderate evidence)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
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
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.
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
Gene: rheb has been classified as Amber List (Moderate Evidence).
Gene: rheb has been classified as Red List (Low Evidence).
Source Victorian Clinical Genetics Services was added to RHEB.
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.
Expert Review Red was added to RHEB. Panel: Intellectual disability
This gene has been classified as Amber List (Moderate Evidence).
Phenotypes for RHEB were set to short stature, macrocephaly, intellectual disability and autism spectrum disorder
Mode of inheritance for RHEB was changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mode of inheritance for RHEB was changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for RHEB were set to macrocephaly and intellectual disability
Publications for RHEB were set to 29051493
RHEB was created by rfoulger
RHEB was added to Intellectual disabilitypanel. Sources: Other
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.