Gene Validity Curation

TBC1D24 - nonsyndromic genetic deafness

Gene: TBC1D24 (HGNC:29203)
Classification - 03/27/2018
Disease: nonsyndromic genetic deafness (MONDO_0019497)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Hearing Loss
Evidence Summary: The TBC1D24 gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 12/13/2017. This association was made using case-level data only. At least 1 missense variant has been reported in humans. TBC1D24 was first associated with this disease in humans in 2014 by two group (Zhang et al. and Azaiez et al.). Other than expression in mouse cochlear hair cells, there is no experimental evidence for dominant disease. Biallelic variants in this gene have been reported to cause recessive nonsyndromic hearing loss and severe neurological disease (epileptic encephalopathy, infantile myoclonic epilepsy, and DOORS syndrome). In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. This classification was approved by the ClinGen Hearing Loss Working Group on 3/27/2018.
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 2
1
1
Azaiez H et al. 2014 Jul (PMID:24729539); Zhang L et al. 2014 Jul (PMID:24729547);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 3 3  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 5.12 2
Azaiez H et al. 2014 Jul (PMID:24729539); Zhang L et al. 2014 Jul (PMID:24729547);
Total Summed LOD Score 5.12    
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) 4
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
1
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Azaiez H et al. 2014 Jul (PMID:24729539); Zhang L et al. 2014 Jul (PMID:24729547);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
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) 1

 


 

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 4 1 5 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
10/04/2018
EXPERT CURATION (DATE)
Limited
03/27/2018
EVIDENCE SUMMARY
The TBC1D24 gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 12/13/2017. This association was made using case-level data only. At least 1 missense variant has been reported in humans. TBC1D24 was first associated with this disease in humans in 2014 by two group (Zhang et al. and Azaiez et al.). Other than expression in mouse cochlear hair cells, there is no experimental evidence for dominant disease. Biallelic variants in this gene have been reported to cause recessive nonsyndromic hearing loss and severe neurological disease (epileptic encephalopathy, infantile myoclonic epilepsy, and DOORS syndrome). In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. This classification was approved by the ClinGen Hearing Loss Working Group on 3/27/2018.