Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

CDH23 : nonsyndromic genetic deafness

HGNC:13733 | 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
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 23
Wagatsuma M et al. 2007 Oct (PMID:17850630); Shahin H et al. 2010 Apr (PMID:19888295); Miyagawa M et al. 2012 Aug 10 (PMID:22899989); Schultz JM et al. 2011 Nov (PMID:21940737);
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) 9
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
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 1 0.5
Schwander M et al. 2009 Mar 31 (PMID:19270079);
Models Non-human model organism 2 0 - 4 4 2 4 4
Schwander M et al. 2009 Mar 31 (PMID:19270079); Hu J et al. 2016 Nov 24 (PMID:27882946);
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) 4.5



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 9 4.5 13.5 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between CDH23 and autosomal recessive nonsyndromic hearing loss was evaluated using the ClinGen Clinical Validity Framework as of 11/30/2017. Variants in CDH23 were first reported in humans with this disease as early as 2007 (Wagatsuma et al. 2007). At least 23 missense and 1 in-frame deletion have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 40 probands in 4 publications (17850630, 19888295, 22899989, 21940737). Variants in this gene segregated with disease in 9 additional family members. Only 9 missense variants have been scored in 9 probands, because the individuals were tested by funduscopy which sufficiently ruled out retinitis pigmentosa (Schultz et al. 2011, 21940737). Of note, this gene has also been implicated in Usher syndrome Type 1. Mostly loss of function variants in CDH23 have been associated with Usher syndrome Type 1, therefore this has been assessed separately as Definitive by the ClinGen Hearing Loss Working Group. The CDH23 and autosomal recessive nonsyndromic hearing loss gene-disease association is supported by multiple mouse models, including models with spontaneous homozygous missense variants (19270079, 27882946, 25732708, 21689626). Expression analysis suggests apoptosis as a mechanism of disease. In summary, CDH23 is definitively associated with autosomal recessive nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 5/22/2018.