Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GJB3 : nonsyndromic genetic deafness

HGNC:4285 | MONDO_0019497
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
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 0 0
Xia JH et al. 1998 Dec (PMID:9843210); López-Bigas N et al. 2001 Apr 15 (PMID:11309368);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Xia JH et al. 1998 Dec (PMID:9843210); Alexandrino F et al. 2004 (PMID:15131355); Mhatre AN et al. 2003 Feb (PMID:12630965); Uyguner O et al. 2003 Jul (PMID:12791041); Yang JJ et al. 2007 Jan 25 (PMID:17259707); Yuan Y et al. 2009 Sep 10 (PMID:19744334); Oh SK et al. 2013 Jan (PMID:22617145); Beck C et al. 2015 Oct (PMID:25214170);
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) 1
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
Expression 0.5 0 - 2 1
Xia JH et al. 1998 Dec (PMID:9843210); López-Bigas N et al. 2001 Apr 15 (PMID:11309368);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4
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 1 1 2 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
An additional 0.5 point awarded to Yuan 2009 Proband 1, however variant is not supported by ClinVar or Allele Registry. The Hearing Loss Expert Panel concluded that this association is Disputed, due to lack of convincing evidence of an association.
The GJB3 gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 3/7/2017. This association was made using case-level data only. Multiple missense and nonsense variants have been reported in humans, however many of these variants are present in high frequency in population databases and/or have no evidence for pathogenicity. 3 variants were considered to have enough evidence to score. GJB3 was first associated with this disease in humans as early as 1998 (Xia et al.). Association is seen in at least 5 probands in 3 publications (12759707, 19744334, 22617145). This gene-disease association is supported by expression studies in rat and mouse cochlea. Of note, this gene has also been implicated in Erythrokeratodermia variabilis. This has been assessed separately. In summary, there is convincing evidence disputing the association between GJB3 and autosomal dominant nonsyndromic hearing loss. More evidence is needed to either support or refute the role GJB3 plays in this disease. This classification was approved by the ClinGen Hearing Loss Working Group on 2/27/2018.