ClinVar

Description

The p.Arg75Trp variant in GJB2 has been identified as the only GJB2 variant in a t least 11 individuals with hearing loss and was not identified in 120 Indian co ntrol chromosomes and 802 Chinese control chromosomes (Richard 1998, Putcha 2007 , Mani 2009, Yuan 2009, Lee 2010, Weegerink 2011, Pang 2014 and LMM unpublished data). Most reported individuals had severe to profound hearing loss that was ei ther congenital or progressive in infancy and some individuals also had palmopla ntar keratoderma. This variant occurred de novo in 3 individuals and was identif ied in three affected parents, which supports that this variant is inherited in a dominant manner (Richard 1998, Yuan 2009, Lee 2010, Weegerink 2011, Pang 2014) . This variant has not been identified in large population studies. Furthermore, Arginine at position 75 is highly conserved across species and other analogous connexin proteins (Deng, 2006). The functional assay demonstrated that the chan ge to a Tryptophan (Trp) at position 75 has a dominant negative affect on the pr otein and disrupts the function of the gap junction (Richard 1998, Maziano 2003, Deng 2006, Zhang 2011) and is important for the postnatal development of the or gan of Corti and normal hearing (Inoshita 2008, Inoshita 2014). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partner s.org/LMM).