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Intellectual disability

Gene: RAC3

Green List (high evidence)

RAC3 (Rac family small GTPase 3)
EnsemblGeneIds (GRCh38): ENSG00000169750
EnsemblGeneIds (GRCh37): ENSG00000169750
OMIM: 602050, Gene2Phenotype
RAC3 is in 3 panels

2 reviews

Catherine Snow (Genomics England)

Comment on list classification: Gene status was changed to Green due to a expert review by Konstantinos Varvagiannis. Sufficient unrelated individuals, from two publications to classify RAC3 as Green. There is no phenotypes associated in OMIM, but is probable in Gene2Phenotype with appropriate phenotype.
Created: 30 May 2019, 12:43 p.m. | Last Modified: 17 Jul 2019, 1:14 p.m.
Panel Version: 0.200

Konstantinos Varvagiannis (Other)

Green List (high evidence)

PMID: 30293988 reports on 5 individuals (from 4 different families) with de novo missense variants in RAC3. All individuals demonstrated structural anomalies on brain MRI (notably agenesis/dysgenesis of the corpus callosum, variable degrees of polymicrogyria and ventricular anomalies) as well as shared non-specific neurological features including abnormal muscular tone, global developmental delay and severe to profound intellectual disability. Feeding difficulties were observed in 4/5 patients.

All variants reported are missense and are presumed to result in constitutive protein activation, as suggested by previous observations either in RAC3 [eg. the p.(Gln61Leu) mutation] or the highly homologous RAC1 and RAC2. According to the authors this is further supported by the fact that Rac3 -/- mice do not show a severe phenotype while missense variants are underrepresented in the ExAC database (z=1.97) as opposed to loss-of-function variants (pLI=0.04 / probability of loss-of-function intolerance).

Of the 3 SNVs reported, 2 variants were in adjacent amino-acid positions [p.(Gln61Leu) and p.(Glu62Lys)]. The latter variant was found in 2 half-sibs born to different fathers, due to suspected maternal gonadal mosaicism (variant absent in all sequencing reads in the maternal DNA sample). The specific variant was also found in a further affected individual from an unrelated family.

Finally, as the authors point out a further individual with de novo RAC3 missense variant [p.(Ala59Gly)] was reported previously in an individual with thin corpus callosum and global developmental delay, although the phenotype was felt to be more reminiscent of Robinow syndrome (PMID: 29276006).

As a result, this gene can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature
Created: 9 Oct 2018, 8:04 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability

Publications

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review
  • Expert Review Green
  • Expert Review Green
  • Expert Review
Phenotypes
  • Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, 618577
  • Abnormality of brain morphology, Abnormal muscle tone, Neurodevelopmental delay, Intellectual disability
  • Abnormality of brain morphology
  • Abnormal muscle tone
  • Neurodevelopmental delay
  • Intellectual disability
OMIM
602050
Clinvar variants
Variants in RAC3
Penetrance
unknown
Publications
Mode of Pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Panels with this gene

History Filter Activity

3 Oct 2019, Gel status: 3

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: RAC3 were changed from Abnormality of brain morphology, Abnormal muscle tone, Neurodevelopmental delay, Intellectual disability; Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability to Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, 618577; Abnormality of brain morphology, Abnormal muscle tone, Neurodevelopmental delay, Intellectual disability; Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability

25 Jul 2019, Gel status: 3

Added New Source, Added New Source, Set Phenotypes, Set publications, Status Update

Catherine Snow (Genomics England)

Source Expert Review Green was added to RAC3. Source Expert Review was added to RAC3. Added phenotypes Abnormality of brain morphology, Abnormal muscle tone, Neurodevelopmental delay, Intellectual disability for gene: RAC3 Publications for gene RAC3 were changed from 30293988; 29276006 to 29276006; 30293988 Rating Changed from No List (delete) to Green List (high evidence)

9 Oct 2018, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance, Set mode of pathogenicity

Konstantinos Varvagiannis (Other)

gene: RAC3 was added gene: RAC3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: RAC3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RAC3 were set to 30293988; 29276006 Phenotypes for gene: RAC3 were set to Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability Penetrance for gene: RAC3 were set to unknown Mode of pathogenicity for gene: RAC3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: RAC3 was set to GREEN