ClinVar

Description

Variant summary: The GJB2 c.250G>C (p.Val84Leu) variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 3/4 in silico tools (SNPs&GO not captured due to low reliability index). The Val84 is proposed to be at the membrane-spanning segments M2/M3 helix interface of the GJB2 protein (Ambrosi_2010). This variant was found in 8/121696 control chromosomes from ExAC at a frequency of 0.0000657, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant is widely reported as a pathogenic variant in literature and is found in ARNSHL patients in homozygous as well as in compound heterozygous state with other known pathogenic variants, including evidence of cosegregation with disease (Kelley_1998, Azaiez_2004, Snoeckx_2005, Zoll_2002, Dalamon_2013, Dahl_2013). Multiple functional studies show that although the V84L mutant channels are able to make gap junctions in mammalian and insect cells, stable in detergent solution and able to allow passage of simple ions (such as LY), they do not allow permeability for molecules larger than simple ions (such as propidium iodide) and reduce permeability to the Ca2+-mobilizing messenger inositol 1,4,5-trisphosphate (Bruzzone_2003, Wang_2003, Beltramello_2005, Zhang_2005, Ambrosi_2010). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Another missense variant at this residue p.V84M has been classified as pathogenic by our lab and others in ClinVar. Taken together, this variant is classified as Pathogenic.