ClinVar Genomic variation as it relates to human health

Variant classified as Uncertain Significance - Favor Pathogenic. The p. Arg186Trp variant in CIB2 has been previously reported in the homozygous state in 1 Caribbean Hispanic individual with hearing loss and segregated with disease in 1 affected sibling, also homozygous for the variant (Patel 2015). This variant has been identified in 0.05% (13/24914) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is present in ClinVar (Variation ID 499480). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied: PM2_Supporting, PP1, PP3, PM3_Supporting.

PS3_supporting, PM1, PM2_supporting, PM3_supporting, PP1_moderate / Modifications from PMID: 30311386 for classification: The genetic causes of hearing loss have not yet been well characterized in the Yoruba population, and the information regarding variant MAF in this population is still limited, so we did not exclude any variant based on their "high" MAF. PP3 criteria was applied even if the REVEL score was below 0.7, if at least two of the pathogenicity prediction algorithms used predicted that the variant was damaging or likely damaging.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 186 of the CIB2 protein (p.Arg186Trp). This variant is present in population databases (rs370359511, gnomAD 0.05%). This missense change has been observed in individuals with non-syndromic sensorineural deafness (PMID: 26426422, 29112224, 34837038). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 499480). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CIB2 function (PMID: 26426422, 28663585). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The CIB2:NM_006383.3:c.556C>T variant has extremely low frequency in gnomAD population databases (PM2), is associated with a recessive disorder, detected in trans with a pathogenic variant, in homozygous state in affected cases (PM3), Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1), reported in ClkniVar in affected individuals (PP5). Here it was found in homozygosis in two affected siblings born from consanguineous marriage.

Published functional studies suggest the p.(R186W) variant results in the loss of calcium sequestering ability relative to wild-type (PMID: 26426422); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28663585, 30174586, 26426422, 29112224, 35440622, 26214305, 35408910, 34837038, 36936795, 36224384, 36223766, 37461484)

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.