Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

CIB2 : Usher syndrome type 1

HGNC:24579 | MONDO_0010168
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
0.5
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
0.5
Riazuddin S et al. 2012 Nov (PMID:23023331);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 0.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Vallone R et al. 2018 Aug 17 (PMID:30174586);
Models Non-human model organism 2 0 - 4 4
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 0.5

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 0.5 0.5 1 NO
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Limited
02/28/2019
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Refuted
02/28/2019
REASON(S) FOR CHANGE
Booth et al. 2017 notes that the p.Glu64Asp variant in the Usher family is only two amino acids away from the p.Arg66Trp variant that has been linked to ARNSHL in three families. All patients studied by Booth et al. 2017 with CIB2 related ARNSHL have normal ocular phenotype no matter the variant impact (null or missense). Booth et al. argue that if CIB2 played a role in Usher syndrome, we would expect to see a retinal phenotype in families segregating with LOF variants. Additionally, loss of known Usher proteins like MYO7A, PCDH15, USH1C, WHRN, USH2A and PDZD7 do not affect the localization of CIB2, and vice versa. Finally, mouse models of Usher caused known Usher genes display congenital profound deafness and vestibular dysfunction, while CIB2 mouse models do not display vestibular disfunction.
EXPERT CURATION (DATE)
Refuted
02/19/2019
EVIDENCE SUMMARY
CIB2 was first reported in relation to autosomal recessive Usher syndrome Type 1 in 2012 (Riazuddin et al., 23023331). One homozygous missense variants in this gene has been reported in at least one proband in one publication (Riazuddin et al. 2012, 23023331). Variants in this gene segregated with disease in 3 additional family members. One additional missense variant has been reported in heterozygosity in an affected individual, however the variant is frequent in population databases and no second pathogenic variant was identified (Fuster-Garcia et al. 2018, 30459346). Booth et al. 2017 (29112224) studied a multi-ethnic cohort of patients with CIB2-related-ARNSHL. All patients in this study have normal ocular phenotype and no vestibular dysfunction regardless of the variant impact. Booth et al. 2017 note that the p.Glu64Asp variant in the Riazuddin Usher family is only two amino acids away from the p.Arg66Trp variant that has been linked to ARNSHL in three families. Booth et al. argue that if CIB2 played a role in Usher syndrome, we would expect to see a retinal and vestibular phenotype in families segregating LOF variants. Michel et al. 2017 (29084757) described 2 families with CIB2-related-ARNSHL. Both families segregate LOF variants and have normal eye phneotype with no pigment deposits. In addition to the variants reported by Booth and Michel, 7 other variants have been linked solely to CIB2-related-ARNSHL (see the CIB2 and ARNSHL gene-disease pair). Michel et al. 2017 also described a CIB2 knockout mouse model. This mouse model displayed congenital profound deafness with no vestibular defect. It also exhibited normal cochlear hair bundle architecture up to postnatal day 7. This is in contrast with all other known USH1 mouse models, which display severe vestibular dysfunction and abnormal cochlear hair bundle architecture starting around postnatal day 3. Other CIB2-murine mutants (28663585 and 29255404) display an identical phenotype to that described by Michel et al. Additionally, it was shown that loss of known USH proteins like MYO7A, PCDH15, USH1C, WHRN, USH2A and PDZD7 does not affect the localization of CIB2, and vice versa. In summary, there is convincing evidence refuting the relationship between CIB2 and autosomal recessive Usher syndrome Type 1, which significantly outweighs the evidence supporting the relationship. This classification was approved by the ClinGen Hearing Loss Working Group on 02/19/2019.