ClinVar

Description

Variant summary: CIB2 c.556C>T (p.Arg186Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251128 control chromosomes. c.556C>T has been reported in the literature as a homozygous genotype in two affected probands each from at-least two distinct families (Carribean and Yoruba Nigerian) with features of Non-syndromic hearing loss (NSHL) and secondary citations by others (example, Patel_2015, Delio_2015, Booth_2019, Adeyemo_2022). Biallelic loss of function variants in CIB2 have been reported to cause autosomal recessive non-syndromic hearing loss (ARNSHL) and not Usher syndrome (USH) (Booth_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no conclusive experimental evidence demonstrating an impact on protein function has been reported, although one study reported p.Arg186Trp mutation affects the calcium binding affinity of CIB2 but did not alter the interactions of CIB2 with Whirlin, nor its targeting to the tips of hair cell stereocilia (Patel_2015). Another study reported this variant as not having notable changes in CIB2 intracellular localization in CHO-K1 cells and no effect on interactions with TMC1 in vitro (Giese_2017). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3, P/LP, n=2). Some submitters cite overlapping but not identical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.