Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GJA1 : nonsyndromic genetic deafness

HGNC:4274 | MONDO_0019497
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
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
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) 0
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
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Liu XZ et al. 2001 Dec 1 (PMID:11741837); Cohen-Salmon M et al. 2004 Apr (PMID:14986102);
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 1 1
Kim AH et al. 2013 Dec (PMID:23817980);
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

 


 

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 0 2 2 NO
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)
Limited
01/10/2019
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Disputed
01/10/2019
REASON(S) FOR CHANGE
Two reported variants were subsequently found to be in a pseudogene. One variant was in very high frequency in gnomAD. An additional variant has no evidence for pathogenicity.
EXPERT CURATION (DATE)
Disputed
01/16/2018
EVIDENCE SUMMARY
GJA1 was first reported in relation to autosomal dominant nonsyndromic hearing loss in 2001 (Liu et al., PMID: 11741837). At least 1 missense and 1 nonsense variant have been reported in humans. Two variants reported (Liu et al. 2001, PMID: 11741837) were subsequently shown to be located in a pseudogene (Pazenkas et al. 2003, PMID: 12457340). Two additional variants have no evidence of pathogenicity (PMIDs: 17259707, 23141803). This gene-disease association is supported by expression studies and a heterozygous knock-out mouse with progressive hearing loss (23817980). Of note, this gene has also been implicated in oculodentodigital dysplasia (ODDD). This association may be assessed separately in the future. In summary, there is convincing evidence disputing the association between GJA1 and autosomal dominant nonsyndromic hearing loss. More evidence is needed to either support or refute the role GJA1 plays in this disease. This classification was approved by the ClinGen Hearing Loss Working Group on 1/16/2018.