Intellectual disability
Gene: RREB1

RREB1 (ras responsive element binding protein 1)
EnsemblGeneIds (GRCh38): ENSG00000124782
EnsemblGeneIds (GRCh37): ENSG00000124782
OMIM: 602209, Gene2Phenotype
RREB1 is in 4 panels

2 reviews

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

Comment on list classification: Of the seven unrelated patients reported with monoallelic single nucleotide variants in RREB1 gene, three were reported with either intellectual disability or global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Created: 5 Aug 2025, 7:06 p.m. | Last Modified: 5 Aug 2025, 7:06 p.m.

Panel Version: 9.55

PMID:38332451 (2024) reported the first patient with RREB1-associated Noonan-like RASopathy. A pathogenic de novo variant in RREB1 gene was identified by whole-genome sequencing and was confirmed by Sanger sequencing in the proband (c.2677del/ p.Ala893Argfs*20). The patient presented with severe intellectual disability, delayed motor skills, short stature, short neck, and distinctive facial dysmorphisms.

PMID:40418122 (2025) reported a cohort of six individuals with a RASopathy phenotype, which include mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay. Global developmental delay was reported in two of these six patients. They were identified with six different truncating RREB1 variants via exome sequencing (five patients with de novo and one patient with paternally inherited variants).

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Created: 5 Aug 2025, 7:02 p.m. | Last Modified: 5 Aug 2025, 7:25 p.m.

Panel Version: 9.55

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
RASopathy, MONDO:0021060

Publications

Created: 5 Aug 2025, 7:02 p.m.
Last Modified: 5 Aug 2025, 7:25 p.m.
Panel version: 9.52

Karen Stals (Royal Devon and Exeter Hospital)

Green List (high evidence)

6 additional individuals with truncating variants in RREB1 gene and a Rasopathy phenotype, features including congenital heart disease, developmental delay, short stature, and dysmorphic facial features (PMID: 40418122). RREB1 encodes a transcriptional repressor of Ras-MAPK signalling. Supporting functional evidence and animal models.
Sources: Literature
Created: 30 Jul 2025, 11:55 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Rasopathy; Noonan-like; developmental disorder

Publications

PMID: 40418122

Created: 30 Jul 2025, 11:55 a.m.

Panel version: 9.51

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Sources

Expert Review Amber

Phenotypes

RASopathy, MONDO:0021060

Tags

Q3_25_promote_green Q3_25_NHS_review

OMIM

602209

Clinvar variants

Variants in RREB1

Penetrance

Complete

Publications

Panels with this gene