Gene Validity Classification Summary

Gene/Disease Pair:

TRIOBP : nonsyndromic sensorineural deafness

MONDO:0012355 | ORPHA:90636 | OMIM:609823
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
0.00
0
Proband with predicted or proven null variant 1.5 0-2 10 0.00 0
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
0.00
0
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
21.00
Shahin H et al. 2006 Jan (PMID:16385458); Riazuddin S et al. 2006 Jan (PMID:16385457); Diaz-Horta O et al. 2012 (PMID:23226338); Fardaei M et al. 2015 Fall (PMID:27014650); Gu X et al. 2015 Jun (PMID:24853665); Yan D et al. 2016 Aug (PMID:27344577);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
0.00
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
1.50
1.5  
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
Shahin H et al. 2006 Jan (PMID:16385458); Riazuddin S et al. 2006 Jan (PMID:16385457);
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Scores PMIDs/Notes
Points/Study Max Points Tally
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
0.00
Hoffmann TJ et al. 2016 Oct (PMID:27764096);
Aggregate Variant Analysis 0-6
0.00
Total Genetic Evidence Points (Maximum 12) 12
Unscored case-control analysis
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2
0.50
2
Kitajiri S et al. 2010 May 28 (PMID:20510926);
Protein Interaction 0.5 0 - 2 0.50
Kitajiri S et al. 2010 May 28 (PMID:20510926);
Expression 0.5 0 - 2 2.00
Shahin H et al. 2006 Jan (PMID:16385458); Riazuddin S et al. 2006 Jan (PMID:16385457); Kitajiri S et al. 2010 May 28 (PMID:20510926);
Functional Alteration Patient cells 1 0 - 2 2
0.00
0
Non-patient cells 0.5 0 - 1 0.00
Models Non-human model organism 2 0 - 4 4 2.00 2
Kitajiri S et al. 2010 May 28 (PMID:20510926);
Cell culture model 1 0 - 2 0.00
Rescue Rescue in human 2 0 - 4
0.00
Rescue in non-human model organism 2 0 - 4
0.00
Rescue in cell culture model 1 0 - 2 0.00
Rescue in patient cells 1 0 - 2 0.00
Total Experimental Evidence Points (Maximum 6) 4

 


 

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 12 4 16 YES
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)
DEFINITIVE
06/09/2017
EXPERT CURATION (DATE)
DEFINITIVE
06/26/2017
The TRIOBP gene has been associated with ARNSHL in 24 probands in 6 publications. 16 unique variants (missense, nonsense, frameshift) have been reported in humans, and variants in this gene segregated with disease in >10 additional family members. TRIOBP was first associated with this disease in humans in 2006 (Riazuddin et al. 2006, Shahin et al. 2006). This gene-disease association is supported by multiple expression and localization studies, studies showing interaction with F-actin in stereocilia, and a deaf mouse model. In summary, TRIOBP is definitively associated with ARNSHL. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group.