GJB2 was first reported in relation to autosomal recessive nonsyndromic hearing loss (DFNB1) in 1997 (Kelsell et al., PMID: 9139825). 8 variants (missense, nonsense, frameshift, and canonical splice site) that have been reported in 6 probands in 4 publications (PMIDs: 9139825, 9482292, 9529365, 16380907) are included in this curation. Variants in GJB2 are found in up to 50% of patients with autosomal recessive nonsyndromic hearing loss (PMID: 16380907). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by experimental evidence. Expression studies in the human cochlea, mouse models with wildtype GJB2 rescuing hearing loss and abnormal inner ear morphology, and in vitro dye transfer and electrical coupling assays demonstrating significant differences between functionally impaired variants and wildtype GJB2 all support this gene-disease relationship (PMIDs: 9507396, 12176036, 15241677, 21876744, 25801282). In summary, there is definitive evidence supporting the relationship between GJB2 and autosomal recessive nonsyndromic hearing loss. 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 Hearing Loss Gene Curation Expert Panel on March 2, 2017. As of September 24, 2024, this record underwent administrative updates to update the SOP version (SOP Version 10.1). No new evidence has been reviewed or added.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.