Gene Validity Classification Summary

Gene/Disease Pair:

TMEM132E : nonsyndromic sensorineural deafness

MONDO:0019588 | ORPHA:90636 |
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
0.00
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
0.25
Li J et al. 2015 Jan (PMID:25331638);
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
0.00
0  
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
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
Aggregate Variant Analysis 0-6
0.00
Total Genetic Evidence Points (Maximum 12) 0.25
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2
0.00
0.5
Protein Interaction 0.5 0 - 2 0.00
Expression 0.5 0 - 2 0.50
Li J et al. 2015 Jan (PMID:25331638);
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 3
Li J et al. 2015 Jan (PMID:25331638);
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
1.00
Li J et al. 2015 Jan (PMID:25331638);
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) 3.5

 


 

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 0.25 3.5 3.75 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
EXPERT CURATION (DATE)
LIMITED
The TMEM132E gene has been associated with ARNSHL in (at least) 1 proband in 1 publications. 1 unique variant (missense) haS been reported in humans, and the variant in this gene segregated with disease in 1 additional family member. TMEM312E was first associated with this disease in humans in 2015 (Li et al.). The mechanism for disease is unknown. This gene-disease association is supported by the expression of the gene in the mouse inner ear, as well as a zebrafish morpholino knockdown and rescue (Li et al. 2015). 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 11/21/2017.