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 |
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1
|
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1
|
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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)*
|
|
CALCULATED CLASSIFICATION (DATE) |
Limited
08/23/2018
|
MODIFY CALCULATED CLASSIFICATION
|
YES
|
MODIFIED CLASSIFICATION (DATE)
|
Disputed
08/23/2018
|
REASON(S) FOR CHANGE
|
An additional 0.5 point awarded to Yuan 2009 Proband 1, however variant is not supported by ClinVar or Allele Registry. The Hearing Loss Expert Panel concluded that this association is Disputed, due to lack of convincing evidence of an association.
|
EXPERT CURATION (DATE) |
Disputed
08/23/2018
|
EVIDENCE SUMMARY |
The GJB3 gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 3/7/2017. This association was made using case-level data only. Multiple missense and nonsense variants have been reported in humans, however many of these variants are present in high frequency in population databases and/or have no evidence for pathogenicity. 3 variants were considered to have enough evidence to score. GJB3 was first associated with this disease in humans as early as 1998 (Xia et al.). Association is seen in at least 5 probands in 3 publications (12759707, 19744334, 22617145). This gene-disease association is supported by expression studies in rat and mouse cochlea. Of note, this gene has also been implicated in Erythrokeratodermia variabilis. This has been assessed separately. In summary, there is convincing evidence disputing the association between GJB3 and autosomal dominant nonsyndromic hearing loss. More evidence is needed to either support or refute the role GJB3 plays in this disease. This classification was approved by the ClinGen Hearing Loss Working Group on 2/27/2018.
|