Gene Validity Classification Summary

Gene/Disease Pair:

GJB2 : syndromic genetic deafness

HGNC:4284 | MONDO_0019589
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hearing Loss EP
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 5
10
10
Janecke AR et al. 2001 Mar (PMID:11354642); Richard G et al. 2002 May (PMID:11912510); Montgomery JR et al. 2004 Sep (PMID:15337980); Weegerink NJ et al. 2011 Mar (PMID:21510145);
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 4
2
2
Richard G et al. 1998 Oct (PMID:9856479); Denoyelle F et al. 1998 May 28 (PMID:9620796); Maestrini E et al. 1999 Jul (PMID:10369869); Wang H et al. 2017 Jan 19 (PMID:28102197);
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 1.5 1.5  
Candidate gene sequencing 12.94 4
Denoyelle F et al. 1998 May 28 (PMID:9620796); Maestrini E et al. 1999 Jul (PMID:10369869); Morlé L et al. 2000 May (PMID:10807696); Wang H et al. 2017 Jan 19 (PMID:28102197);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 12.94    
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) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
0.5
0.5
Deng Y et al. 2006 Oct (PMID:16945493);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
1.5
Non-patient cells 0.5 0 - 1 2 1.5
Zhang J et al. 2011 Jun (PMID:21040787); Matos TD et al. 2008 Jun (PMID:18472371);
Models Non-human model organism 2 0 - 4 4 2 4 4
Maeda Y et al. 2005 Jun 15 (PMID:15857852); Bosen F et al. 2015 Jul 8 (PMID:26070424);
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) 6

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
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
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
12/14/2018
EXPERT CURATION (DATE)
Definitive
06/26/2018
EVIDENCE SUMMARY
GJB2 was first reported in relation to autosomal dominant hearing loss with or without skin findings in 1998 (Richard et al., 9856479). At least 30 missense variants have been reported in humans. Association is seen in at least 11 probands in 11 publications (PMIDs: 11354642, 11912510, 15337980, 20937258, 21868108, 9856479, 9620796, 10369869, 10807696, 16226720, 28102197). Variants in this gene segregated with disease in 49 additional family members. Much more evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. This gene-disease association is supported by animal models, expression studies, in vitro functional assays, and biochemical functional studies, which support a dominant-negative mechanism of disease. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern for AD nonsyndromic hearing loss, AD keratitis ichthyosis deafness (KID) and AD palmoplantar keratoderma (PPK) with deafness. It is possible that these phenotypes exist on a spectrum of disease. In summary, GJB2 is definitively associated with autosomal dominant Hearing Loss with or without Skin Findings. This classification was approved by the ClinGen Hearing Loss Working Group on 6/26/2018.