Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

OTOA : nonsyndromic genetic deafness

HGNC:16378 | MONDO_0019497
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 4
Zwaenepoel I et al. 2002 Apr 30 (PMID:11972037); Shahin H et al. 2010 Apr (PMID:19888295); Sloan-Heggen CM et al. 2016 Apr (PMID:26969326);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 5
Lee K et al. 2013 Sep (PMID:23173898); Ammar-Khodja F et al. 2015 May (PMID:26029705); Walsh T et al. 2006 Jan (PMID:16460646);
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 7.8 2
Lee K et al. 2013 Sep (PMID:23173898); Walsh T et al. 2006 Jan (PMID:16460646);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 7.8    
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 1
Haraksingh RR et al. 2014 Dec 20 (PMID:25528277);
Total Genetic Evidence Points (Maximum 12) 12
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 1 0.5
Zwaenepoel I et al. 2002 Apr 30 (PMID:11972037);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 2
Lukashkin AN et al. 2012 Nov 20 (PMID:23129639);
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) 2.5



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 2.5 14.5 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between OTOA and autosomal recessive nonsyndromic hearing loss was evaluated using the ClinGen Clinical Validity Framework as of 11/10/2017. Variants in OTOA were first reported in humans with this disease as early as 2002 (Zwaenepoel et al.). At least 10 variants (e.g. missense, splice-site, large deletion, whole gene deletion) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level, case-control, and experimental data. Variants in this gene have been reported in at least 9 probands in 6 publications (PMIDs: 11972037, 19888295, 23173898, 16460646, 26029705, 26969326). Variants in this gene segregated with disease in at least 17 additional family members. This gene-disease relationship has been studied in at least 1 case-control studies (PMID 25528277) at the aggregate variant level. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by a relevant expression studies as well as a knockout mouse model. OTOA also has a pseudogene, which could contaminate the sequencing of the gene. Caution should be used when assessing the missense variants reported in OTOA, because they could be in the pseudogene. In summary, OTOA is definitively associated with autosomal recessive nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 5/1/2018.