Submission Details

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.