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Intellectual disability

Gene: ARHGEF6

Red List (low evidence)
ARHGEF6 (Rac/Cdc42 guanine nucleotide exchange factor 6)
EnsemblGeneIds (GRCh38): ENSG00000129675
EnsemblGeneIds (GRCh37): ENSG00000129675
OMIM: 300267, Gene2Phenotype
ARHGEF6 is in 2 panels

7 reviews

Arina Puzriakova (Genomics England Curator)

PMID: 22511880 (2012) - a variant in the ARHGEF6 gene (p.I444N) was identified in a male patient with autism. However, this individual harboured variants in other genes (UBE3B) that were likely to explain their phenotype so conclusions about the consequence of the ARHGEF6 variant cannot be made in this case.

Comment on publications: PMIDs: 22511880 (2012) and 26177020 (2015) were identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Created: 26 Feb 2024, 12:19 p.m. | Last Modified: 26 Feb 2024, 12:21 p.m.
Panel Version: 5.461
Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark
Created: 17 Aug 2020, 9:21 a.m. | Last Modified: 17 Aug 2020, 9:21 a.m.
Panel Version: 3.250
Created: 17 Aug 2020, 9:21 a.m.
Last Modified: 26 Feb 2024, 12:21 p.m.
Panel version: 5.460

Zornitza Stark (Australian Genomics)

Red List (low evidence)

We have rated this gene as Red considering some of the evidence was from cytogenetic abnormalities and other reported variants are now found to be present in the population at high frequency.
Created: 29 Jan 2020, 1:36 a.m. | Last Modified: 29 Jan 2020, 1:36 a.m.
Panel Version: 3.0

Phenotypes
MENTAL RETARDATION X-LINKED TYPE 46

Created: 29 Jan 2020, 1:36 a.m.
Last Modified: 29 Jan 2020, 1:36 a.m.
Panel version: 3.0

Louise Daugherty (Genomics England Curator)

Comment on list classification: demoted from Green to Amber
Created: 2 Apr 2019, 10:09 a.m.
Created: 2 Apr 2019, 10:09 a.m.

Panel version: 2.790

Richard Scott (Genomics England Curator)

Red List (low evidence)

Literature review identifies lack of clarity about published data on this gene. As per note in OMIM entry:

ARHGEF6, IVS1AS, T-C, -11 (rs140322310)
RCV000012185
This variant, formerly titled MENTAL RETARDATION, X-LINKED 46, has been reclassified based on a review of the ExAC database by Hamosh (2018).
In affected males in a large Dutch family with nonspecific X-linked mental retardation (MRX46; 300436), Kutsche et al. (2000) identified a mutation in the ARHGEF6 gene. The base change IVS1-11T-C had a marginal effect on the predicted splicing efficiency but was not detected in 170 control chromosomes. In affected males, RT-PCR amplification demonstrated products of 2 different sizes: a larger amplicon corresponding to the wildtype fragment, and a smaller amplicon in which exon 1 was spliced to exon 3. Thus, all mentally retarded males in the MRX46 family exhibited enhanced skipping of exon 2.
Hamosh (2018) found that the IVS1-11T-C variant (rs140322310) was present in 53 hemizygotes in the ExAC database (November 21, 2018), suggesting that the variant is not pathogenic
Created: 26 Mar 2019, 2:33 p.m.
Literature review identifies lack of clarity about published data on this gene. As per note in OMIM entry:

ARHGEF6, IVS1AS, T-C, -11 (rs140322310)
RCV000012185
This variant, formerly titled MENTAL RETARDATION, X-LINKED 46, has been reclassified based on a review of the ExAC database by Hamosh (2018).
In affected males in a large Dutch family with nonspecific X-linked mental retardation (MRX46; 300436), Kutsche et al. (2000) identified a mutation in the ARHGEF6 gene. The base change IVS1-11T-C had a marginal effect on the predicted splicing efficiency but was not detected in 170 control chromosomes. In affected males, RT-PCR amplification demonstrated products of 2 different sizes: a larger amplicon corresponding to the wildtype fragment, and a smaller amplicon in which exon 1 was spliced to exon 3. Thus, all mentally retarded males in the MRX46 family exhibited enhanced skipping of exon 2.
Hamosh (2018) found that the IVS1-11T-C variant (rs140322310) was present in 53 hemizygotes in the ExAC database (November 21, 2018), suggesting that the variant is not pathogenic
Created: 26 Mar 2019, 2:32 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
300436

Created: 26 Mar 2019, 2:32 p.m.

Panel version: 2.787

Ellen McDonagh (Genomics England Curator)

Comment on publications: PMID: 21989057 - mouse model of gene knockout have an imbalance in activity of different Rho GTPases, and exhibited impaired spatial and complex learning and less behavioral control in mildly stressful situations. PMID: 20861843 - report a Xq26.2-Xq26.3 duplication in two brothers with severe mental retardation, hypotonia, growth delay, craniofacial disproportion and dental malocclusion. This encompasses 24 known genes, including ARHGEF6, PHF6, HPRT1 and SLC9A6.
Created: 15 May 2018, 12:47 p.m.
Created: 15 May 2018, 12:45 p.m.

Panel version: 2.62

Caroline Wright (Sanger)

Green List (high evidence)

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
MENTAL RETARDATION X-LINKED TYPE 46

Publications

  • 0

Created: 5 Nov 2017, 2:42 a.m.

Panel version: 0

Lu Raymond (university of cambridge )

Green List (high evidence)

Created: 23 Feb 2016, 10:59 a.m.

Panel version: 0.306

Details

Mode of Inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Expert Review Red
  • Victorian Clinical Genetics Services
  • Radboud University Medical Center, Nijmegen
  • Illumina TruGenome Clinical Sequencing Services
Phenotypes
  • Intellectual developmental disorder, X-linked 46, OMIM:300436
OMIM
300267
Clinvar variants
Variants in ARHGEF6
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

26 Feb 2024, Gel status: 1

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: ARHGEF6 were set to 21989057; 20861843; 17304053; 11017088; 26177020; 22511880

26 Feb 2024, Gel status: 1

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: ARHGEF6 were set to 21989057; 20861843; 17304053; 11017088; 26177020

26 Feb 2024, Gel status: 1

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: ARHGEF6 were set to 21989057; 20861843; 17304053; 11017088

26 Feb 2024, Gel status: 1

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: ARHGEF6 were changed from Mental retardation, X-linked 46, 300436; Mental Retardation, X-linked; MENTAL RETARDATION X-LINKED TYPE 46 to Intellectual developmental disorder, X-linked 46, OMIM:300436

12 Oct 2020, Gel status: 1

Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source Expert Review Red was added to ARHGEF6. Rating Changed from Amber List (moderate evidence) to Red List (low evidence)

2 Apr 2019, Gel status: 2

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: arhgef6 has been classified as Amber List (Moderate Evidence).

28 Sep 2018, Gel status: 4

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to ARHGEF6.

15 May 2018, Gel status: 3

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for ARHGEF6 were set to 21989057; 20861843; 17304053; 11017088

15 May 2018, Gel status: 3

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for ARHGEF6 were set to 21989057; 20861843; 17304053

15 May 2018, Gel status: 3

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for ARHGEF6 were set to 21989057; 20861843

15 May 2018, Gel status: 3

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for ARHGEF6 were set to 21989057; 20861843

12 Mar 2018, Gel status: 3

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.

13 Nov 2015, Gel status: 4

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 4

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

Set Mode of Inheritance, Added New Source

Ellen McDonagh (Genomics England Curator)

ARHGEF6 was added to Intellectual disabilitypanel. Source: Expert Review Green Model of inheritance for gene ARHGEF6 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females

24 Jun 2015, Gel status: 2

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene ARHGEF6 was changed to X-LINKED: hemizygous mutation in males, may be caused by monoallelic mutations in females

24 Jun 2015, Gel status: 2

Added New Source

Ellen McDonagh (Genomics England Curator)

ARHGEF6 was added to Intellectual disabilitypanel. Sources: Illumina TruGenome Clinical Sequencing Services,Radboud University Medical Center, Nijmegen

24 Jun 2015, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

ARHGEF6 was added to Intellectual disabilitypanel. Sources: Illumina TruGenome Clinical Sequencing Services,Radboud University Medical Center, Nijmegen