Gene Validity Classification Summary

Gene/Disease Pair:

GJB3 : erythrokeratodermia variabilis

HGNC:4285 | MONDO_0017851
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
4
4
Richard G et al. 2000 Mar (PMID:10798362); Richard G et al. 1998 Dec (PMID:9843209); Renner R et al. 2008 Jun (PMID:18482034); Morley SM et al. 2005 Jun (PMID:15948974);
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 10
2.5
2.5
Richard G et al. 1998 Dec (PMID:9843209); Wang W et al. 2012 Dec (PMID:22681493); Glatz M et al. 2011 Oct (PMID:21879244); Morley SM et al. 2005 Jun (PMID:15948974); Ikeya S et al. 2013 May (PMID:23442023); Takeichi T et al. 2016 May (PMID:26632638); Wilgoss A et al. 1999 Dec (PMID:10594760); Otaguchi R et al. 2014 Nov (PMID:25297803); Liu H et al. 2012 Apr (PMID:21950330); Scott CA et al. 2011 Jan (PMID:21188847);
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 1  
Candidate gene sequencing 4.52 2
Richard G et al. 1998 Dec (PMID:9843209); Morley SM et al. 2005 Jun (PMID:15948974);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 4.52    
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) 7.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2 1 0.5
Tang C et al. 2015 Nov 1 (PMID:26251042);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
2
Non-patient cells 0.5 0 - 1 4 2
Diestel S et al. 2002 Aug 23 (PMID:12176042); Tang C et al. 2015 Nov 1 (PMID:26251042); Chi J et al. 2012 Feb 29 (PMID:22393412);
Models Non-human model organism 2 0 - 4 4 3 2 2
Tang C et al. 2015 Nov 1 (PMID:26251042); Pyati UJ et al. 2011 Sep 13 (PMID:21920315);
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) 4.5

 


 

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 7.5 4.5 12 NO
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)
Strong
12/04/2018
EXPERT CURATION (DATE)
Strong
03/05/2018
EVIDENCE SUMMARY
The GJB3 gene has been associated with autosomal dominant erythrokeratodermia variabilis using the ClinGen Clinical Validity Framework as of 3/5/2018. This association was made using case-level data. At least 8 missense variants have been reported in humans. Some variants are reported de novo, however paternity and maternity were not confirmed in most cases. GJB3 was first associated with this disease in humans as early as 1998 (Richard et al.). Association is seen in at least 15 probands in 12 publications (9843209, 10798362, 22681493, 21879244, 18482034, 15948974, 23442023, 26632638, 10594760, 25297803, 21950330, 21188847). Variants in this gene segregated with disease in 23 additional family members. Of note, this gene has also been implicated in autosomal dominant nonsyndromic hearing loss. This has been assessed separately as Disputed. The GJB3 and autosomal dominant erythrokeratodermia variabilis association is supported by mouse and zebrafish models which have recapitulated partial phenotypes of EKV. In summary, there is strong evidence to support the association between GJB3 and autosomal dominant erythrokeratodermia variabilis. Additional reports in humans are needed to reach a definitive classification. This classification was approved by the ClinGen Hearing Loss Working Group on 3/5/2018.