Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

CLDN14 : nonsyndromic genetic deafness

HGNC:2035 | 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 3
5
9.5
Wilcox ER et al. 2001 Jan 12 (PMID:11163249); Lee K et al. 2012 Feb (PMID:22246673); Manzoli GN et al. 2016 Nov (PMID:27870113);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 13
4.5
Wilcox ER et al. 2001 Jan 12 (PMID:11163249); Bashir R et al. 2010 Nov (PMID:20811388); Lee K et al. 2012 Feb (PMID:22246673); Bashir ZE et al. 2013 Feb (PMID:23235333); Pater JA et al. 2017 Jan (PMID:27838790); Wattenhofer M et al. 2005 Jun (PMID:15880785);
Segregation Evidence   Summed LOD Family Count 2 2  
Candidate gene sequencing 11.43 2
Wilcox ER et al. 2001 Jan 12 (PMID:11163249); Bashir R et al. 2010 Nov (PMID:20811388);
Exome/genome or all genes sequenced in linkage region 3.16 1
Pater JA et al. 2017 Jan (PMID:27838790);
Total Summed LOD Score 14.59    
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) 11.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Shiraiwa Y et al. 2018 Jun (PMID:28811056);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Ben-Yosef T et al. 2003 Aug 15 (PMID:12913076);
Models Non-human model organism 2 0 - 4 4 1 2 2
Ben-Yosef T et al. 2003 Aug 15 (PMID:12913076);
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

 


 

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 11.5 3 14.5 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
11/27/2018
EXPERT CURATION (DATE)
Definitive
05/01/2018
EVIDENCE SUMMARY
The relationship between CLDN14 and autosomal recessive nonsyndromic hearing loss was evaluated using the ClinGen Clinical Validity Framework as of 11/17/2017. Variants in CLDN14 were first reported in humans with this disease as early as 2001 (Wilcox et al.). At least 7 variants (e.g. missense, in-frame indel, nonsense, frameshift) 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 12 probands in 6 publications (11163249, 20811388, 22246673, 23235333, 27870113, 27838790). Variants in this gene segregated with disease in at least 49 additional family members. Many of the reported variants are believed to be founder variants from Pakistan and Newfoundland and Labrador Province. This gene-disease association is supported by a knockout mouse model and additional expression and functional alteration evidence. In summary, CLDN14 is definitively associated with autosomal recessive nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 5/1/2018.