The GJB3 gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 3/7/2017. This association was made using case-level data only. Multiple missense and nonsense variants have been reported in humans, however many of these variants are present in high frequency in population databases and/or have no evidence for pathogenicity. 3 variants were considered to have enough evidence to score. GJB3 was first associated with this disease in humans as early as 1998 (Xia et al.). Association is seen in at least 5 probands in 3 publications (12759707, 19744334, 22617145). This gene-disease association is supported by expression studies in rat and mouse cochlea. Of note, this gene has also been implicated in Erythrokeratodermia variabilis. This has been assessed separately. In summary, there is convincing evidence disputing the association between GJB3 and autosomal dominant nonsyndromic hearing loss. More evidence is needed to either support or refute the role GJB3 plays in this disease. This classification was approved by the ClinGen Hearing Loss Working Group on 2/27/2018.
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).
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