Gene Validity Classification Summary

Gene/Disease Pair:

COCH : nonsyndromic genetic deafness

HGNC:2180 | MONDO_0019497
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
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 12
8.5
7
Bischoff AM et al. 2005 Sep (PMID:16151338); Gu X et al. 2016 Dec 27 (PMID:28116169); Wang Q et al. 2017 Jan 18 (PMID:28099493); Robertson NG et al. 1998 Nov (PMID:9806553); Pauw RJ et al. 2007 May (PMID:17561763); Hildebrand MS et al. 2010 Dec (PMID:21046548); Jung J et al. 2015 Dec (PMID:26256111); Gao J et al. 2013 May (PMID:22931125); Cho HJ et al. 2012 Nov (PMID:22610276); Yuan HJ et al. 2008 Apr (PMID:18312449);
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 6.32 1
Bischoff AM et al. 2005 Sep (PMID:16151338);
Total Summed LOD Score 6.32    
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) 10
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 2 1.5
Robertson NG et al. 1998 Nov (PMID:9806553); Robertson NG et al. 2006 Apr 1 (PMID:16481359);
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
Robertson NG et al. 2008 Nov 1 (PMID:18697796);
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) 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 10 3.5 13.5 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)
Definitive
10/04/2018
EXPERT CURATION (DATE)
Definitive
01/05/2018
EVIDENCE SUMMARY
The COCH gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 12/28/2017. This association was made using case-level data only. At least 11 missense variants have been reported in humans. COCH was first associated with this disease in humans as early as 1998 (Robertson et al.). Association is seen in at least 13 probands in 11 publications (16151338, 28116169, 28099493, 9806553, 17561763, 21046548, 26256111, 22931125, 22610276, 18312449, 28733840). Variants in this gene segregated with disease in >50 additional family members. This gene-disease association is supported by a knock-in mouse model with the p.Gly88Glu variant, expression in human postmortem temporal bones and chicken cochlea, as well as approved localization and Western blot assessment. In summary, COCH is definitively associated with autosomal dominant nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 1/5/2018.