Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GJB6 : nonsyndromic genetic deafness

HGNC:4288 | MONDO_0019497
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max 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
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 Evidence of segregation in one or more families   Sequencing Method 0-3 3
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total 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
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2 0
Ahmad S et al. 2003 Jul 25 (PMID:12859965);
Expression 0.5 0 - 2 0
Forge A et al. 2003 Dec 8 (PMID:14595769); Liu W et al. 2016 July (PMID:26941236);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 0 0
Teubner B et al. 2003 Jan 1 (PMID:12490528);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Ahmad S et al. 2007 Jan 23 (PMID:17227867); Qu Y et al. 2012 Jan 6 (PMID:22142852);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 0



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 0 0 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
No Classification
See Evidence Summary for full Refuted explanation.
The GJB6 gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 12/21/2017​. The GJB6-D13S1830 deletion is a relatively common disease allele in many populations and is classified as pathogenic for hearing loss, frequently identified in homozygosity or in trans with a pathogenic GJB2 variant. This is a deletion of approximately 309kb of DNA including the 5' end of GJB6 and a region upstream of both GJB6 and the GJB2 gene. It has been proposed that GJB6 and GJB2 are co-regulated by a cis-acting element (Ahmad 2007 PMID 17227867). Their protein products, connexin 30 and 26 (Cx30 and Cx26), respectively, co-localize in the supporting cells of mouse cochlea (Ahmad 2003 PMID 12859965; Forge 2003 PMID 14595769) but not human cochlea (Liu 2016 PMID 26941236). Deletion of the GJB6 gene, including surrounding regulatory regions, in mice causes hearing loss (Teubner 2003 PMID 12490528). Exogenous Cx30 and Cx26 could both rescue the hearing loss in this mouse (Ahmad 2007 PMID 17227867; Qu 2012 PMID 22142852). However, an independent mouse model with only the coding sequence of GJB6 deleted and no surrounding sequence deleted had normal hearing, suggesting that the regulatory region 5' of GJB6 but not the gene itself is necessary for normal hearing in mice. Furthermore, many deletions upstream of both GJB6 and GJB2 are pathogenic for hearing loss without disruption of GJB6 (Wilch 2010 PMID 20236118; Abou Tayoun 2016 PMID 26444186). This gene has also been implicated in Clouston syndrome. This association has been​ assessed separately. In summary, there is convincing evidence refuting the association between GJB6 and autosomal recessive nonsyndromic hearing loss, which significantly outweighs the evidence supporting the association. This classification was approved by the ClinGen Hearing Loss Working Group on 4/17/2018.