Gene Validity Curation

GJB1 - Charcot-Marie-Tooth disease X-linked dominant 1

Gene: GJB1 (HGNC:4283)
Classification - 01/14/2020
Disease: Charcot-Marie-Tooth disease X-linked dominant 1 (MONDO_0010549)
Mode of Inheritance: X-linked inheritance (HP:0001417)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Charcot-Marie-Tooth EP Contributors:
  • UNC Biocuration Core
Evidence Summary: GJB1 was first reported in relation to Charcot Marie Tooth (CMT) disease in 1993 (Bergoffen et al., 1993; PMID: 8266101) At least 450 unique variants, including missense, nonsense, frameshift, and indels have been reported in humans (reviewed in Bortolozzi, 2018; PMID: 30042657; Kleopa et al., 2012; PMID: 22771394). There are a variant databases describing GJB1 variants of interest in CMT, and include (1) the Inherited Neuropathy Variant Database (greater than 700 GJB1 variants; URL: http://hihg.med.miami.edu/code/http/cmt/public_html/index.html#/), and (2) the GJB1 Gene homepage on LOVD (URL: https://databases.lovd.nl/shared/genes/GJB1). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This gene-disease relationship has been studied for over 20 years, therefore a significant amount of case-level data and segregation is available, however the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by expression studies and animal models. GJB1 has 2 exons of which the entirety of the protein coding region is encoded by exon 2, therefore nonsense variants are not predicted to undergo nonsense mediated decay. The molecular mechanism associated with CMT is loss of functional gap junction function, including destabilization or loss of hetero- and homo-dimerization with connexins, and perturbation of ion and small molecule exchange across the multilamellar layers of myelin sheath (reviewed in Scherer and Wrabetz, 2008; PMID: 18803325; Nualart-Marti et al., 2013; PMID: 22326946). In summary, GJB1 is DEFINITIVELY associated with x-linked Charcot Marie Tooth disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Charcot Marie Tooth Gene Curation Expert Panel on Jan 14, 2020.
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 1
0.5
0.5
Di Iorio G et al. 2000 Apr (PMID:10938190);
Proband with predicted or proven null variant 1.5 0-2 10 5 5.5 5.5
Ionasescu V et al. 1996 Jun 14 (PMID:8737658); Karadimas C et al. 1999 (PMID:10220155);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 4
5.5
5.5
Ionasescu V et al. 1996 Jun 14 (PMID:8737658); Karadimas C et al. 1999 (PMID:10220155);
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 8.12 2
Ionasescu V et al. 1996 Jun 14 (PMID:8737658);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 8.12    
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
2
Scherer SS et al. 1995 Dec (PMID:8613761);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 1.5
Scherer SS et al. 1995 Dec (PMID:8613761);
Functional Alteration Patient cells 1 0 - 2 2
1
Non-patient cells 0.5 0 - 1 1 1
Omori Y et al. 1996 Jun (PMID:8816997);
Models Non-human model organism 2 0 - 4 4 1 4 4
Sargiannidou I et al. 2009 Apr 15 (PMID:19369543);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Scherer SS et al. 2005 Feb 9 (PMID:15703409);
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
02/07/2020
EXPERT CURATION (DATE)
Definitive
01/14/2020
EVIDENCE SUMMARY
GJB1 was first reported in relation to Charcot Marie Tooth (CMT) disease in 1993 (Bergoffen et al., 1993; PMID: 8266101) At least 450 unique variants, including missense, nonsense, frameshift, and indels have been reported in humans (reviewed in Bortolozzi, 2018; PMID: 30042657; Kleopa et al., 2012; PMID: 22771394). There are a variant databases describing GJB1 variants of interest in CMT, and include (1) the Inherited Neuropathy Variant Database (greater than 700 GJB1 variants; URL: http://hihg.med.miami.edu/code/http/cmt/public_html/index.html#/), and (2) the GJB1 Gene homepage on LOVD (URL: https://databases.lovd.nl/shared/genes/GJB1). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This gene-disease relationship has been studied for over 20 years, therefore a significant amount of case-level data and segregation is available, however the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by expression studies and animal models. GJB1 has 2 exons of which the entirety of the protein coding region is encoded by exon 2, therefore nonsense variants are not predicted to undergo nonsense mediated decay. The molecular mechanism associated with CMT is loss of functional gap junction function, including destabilization or loss of hetero- and homo-dimerization with connexins, and perturbation of ion and small molecule exchange across the multilamellar layers of myelin sheath (reviewed in Scherer and Wrabetz, 2008; PMID: 18803325; Nualart-Marti et al., 2013; PMID: 22326946). In summary, GJB1 is DEFINITIVELY associated with x-linked Charcot Marie Tooth disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Charcot Marie Tooth Gene Curation Expert Panel on Jan 14, 2020.