Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

ARHGEF6 : non-syndromic X-linked intellectual disability

HGNC:685 | MONDO_0019181
Mode of Inheritance: X-linked inheritance (HP:0001417)
Expert Panel: Harvard/Geisinger Biocuration Core
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 3
Kutsche K et al. 2000 Oct (PMID:11017088); Tarpey PS et al. 2009 May (PMID:19377476);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 0.1
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0
Ramakers GJ et al. 2012 Jan 15 (PMID:21989057);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 1 1
Ramakers GJ et al. 2012 Jan 15 (PMID:21989057);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 1



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 0.1 1 1.1 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
ARHGEF6 was evaluated for evidence supporting its purported relationship with X-linked nonsyndromic intellectual disability (ID) using the ClinGen Clinical Validity Framework. The relationship was first reported in 2000 by Kutsche et al. Kutsche described a male with ID and an apparently balanced translocation between chromosomes X and 21 inherited from his unaffected mother. Using genomic walking, the authors were able to show that "the translocation is reciprocal but molecularly unbalanced, with a 10-bp deletion on the X chromosome and a 9-bp deletion in the β-satellite DNA on chromosome 21." No additional studies were done to determine the effects on ARHGEF6 expression. Notably, the mother did not show preferential inactivation of her normal X. The authors went on to screen 119 additional patients with nonspecific ID for variants in ARHGEF6, and identified a variant within the first intron in all (tested) affected males in a large Dutch family. This particular variant has been found in a higher than expected frequency in the general population, and is therefore not considered evidence in this evaluation. Two additional missense variants were described in Tarpey et al. (2009); one of these is also observed at relatively high frequencies in the general population and was not considered as evidence in this evaluation. The other variant is observed in gnomAD, though at a low enough frequency to not completely rule out a possible role in disease; given the lack of supporting functional data, however, this variant is scored only at 0.1 points. Of note, there is also a report of two brothers with intellectual disability and a multi-gene duplication involving ARHGEF6 (Madrigal et al. 2010, PMID: 20861843; family also described in Madrigal et al. 2007, PMID:17304053); this is not counted as evidence due to the multi-gene nature of the copy number variant. In terms of experimental evidence, there is a knockout mouse model that does appear to show some deficits in complex spatial learning; however, given that the mechanism of disease is unclear, and no null variants have been reported in association with human disease, it is unclear whether this particular mouse model recapitulates the human disease state. In summary, there is limited evidence to support this gene-disease association. More evidence is needed to support a causal role. Though two specific variants have been refuted, this does not necessarily rule out a role for this gene in disease.