Gene Validity Classification Summary

Gene/Disease Pair:

OTOG : nonsyndromic genetic deafness

HGNC:8516 | MONDO_0019497
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss EP
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 2
4
4
Schraders M et al. 2012 Nov 2 (PMID:23122587);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
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) 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
1.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 3 1.5
Schraders M et al. 2012 Nov 2 (PMID:23122587); Cohen-Salmon M et al. 1997 Dec 23 (PMID:9405633); El-Amraoui A et al. 2001 Aug (PMID:11506947);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 3 5 4
El Hakam Kamareddin C et al. 2015 Nov 25 (PMID:26636018); Roberts R et al. 2017 Jun (PMID:28332011); Simmler MC et al. 2000 Feb (PMID:10655058);
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) 5.5

 


 

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 4 5.5 9.5 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)
Moderate
10/04/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Definitive
10/04/2018
REASON(S) FOR CHANGE
The Partners Laboratory for Molecular Medicine has six additional unpublished internal cases of probands with mild sensorineural hearing loss and homozygous or compound heterozygous loss of function variants. The addition of these cases brings the final classification to Definitive.
EXPERT CURATION (DATE)
Definitive
06/28/2018
EVIDENCE SUMMARY
The OTOG gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 9/28/2017. This association was made using case-level data only. At least 3 variants (missense, nonsense, & frameshift) have been published in humans (23122587). Association is seen in at least 2 probands in 1 publication (23122587). Variants in this gene segregated with disease in 4 additional family members. Additionally, the Partners Laboratory for Molecular Medicine has six unpublished internal cases of probands with mild sensorineural hearing loss and homozygous or compound heterozygous loss of function variants. This gene-disease association is supported by mouse and zebrafish models and expression studies. In summary, OTOG is definitively associated with autosomal recessive nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 6/28/2018.