ClinVar Miner

Submissions for variant NM_006383.4(CIB2):c.556C>T (p.Arg186Trp) (rs370359511)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000596997 SCV000704978 uncertain significance not provided 2017-01-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001195601 SCV001366000 uncertain significance not specified 2019-05-22 criteria provided, single submitter clinical testing 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.
Laboratory of Prof. Karen Avraham,Tel Aviv University RCV001290343 SCV001478331 pathogenic Deafness, autosomal recessive 48 2021-01-31 criteria provided, single submitter research
Invitae RCV000596997 SCV001517809 uncertain significance not provided 2020-08-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 186 of the CIB2 protein (p.Arg186Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs370359511, ExAC 0.06%). This variant has been observed in individual(s) with non-syndromic sensorineural deafness (PMID: 26426422, 29112224). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 499480). This variant has been reported to affect CIB2 protein function (PMID: 26426422, 28663585). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
National Institute on Deafness and Communication Disorders,National Institutes of Health RCV001328027 SCV001519360 likely pathogenic Childhood onset hearing loss 2021-07-08 criteria provided, single submitter research 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.

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