Gene Validity Classification Summary

Gene/Disease Pair:

GJB6 : Clouston syndrome

HGNC:4288 | MONDO_0007510
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 1
1
1
Baris HN et al. 2008 Dec (PMID:18717672);
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
6
6
Grifa A et al. 1999 Sep (PMID:10471490); Nemoto-Hasebe I et al. 2009 Aug (PMID:19416251); Yang JJ et al. 2007 Jan 25 (PMID:17259707); Pandey N et al. 2016 Jan (PMID:26620415); Liu YT et al. 2015 Oct (PMID:25808784); Lamartine J et al. 2000 Oct (PMID:11017065); Smith FJ et al. 2002 Mar (PMID:11874494); Jan AY et al. 2004 May (PMID:15140211); Yang R et al. 2016 Aug (PMID:27137747); Fujimoto A et al. 2013 Feb (PMID:23219093);
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 1.5 1.5  
Candidate gene sequencing 5.72 1
Lamartine J et al. 2000 Oct (PMID:11017065);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 5.72    
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) 8.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 2
Fujimoto A et al. 2013 Feb (PMID:23219093); Berger AC et al. 2014 Apr 15 (PMID:24522190);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4
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 8.5 2 10.5 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)
Moderate
10/04/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Definitive
10/04/2018
REASON(S) FOR CHANGE
Expert review upgraded the GJB6-Clouson syndrome association to Definitive after reviewing the available evidence.
EXPERT CURATION (DATE)
Definitive
04/17/2018
EVIDENCE SUMMARY
The GJB6 gene has been associated with autosomal dominant Clouston syndrome using the ClinGen Clinical Validity Framework as of 4/13/18. This association was made using case-level data. At least 8 missense variants have been reported in humans. GJB6 was first associated with this disease in humans as early as 2000 (Lemartine et al.​). Association is seen in at least 13 probands in 8 publications (11017065, 23219093, 11874494, 18717672, 27137747, 25808784, 19416251, 26620415). Variants in this gene segregated with disease in 65 additional family members. The GJB6 and autosomal dominant Clouston syndrome association is supported by expression studies. Of note, this gene has also been implicated in nonsyndromic hearing loss. Autosomal recessive nonsyndromic hearing loss has been​ assessed separately. There was not enough evidence to split out and curate for autosomal dominant nonsyndromic hearing loss, however it should be noted this curation did not score any AD nonsyndromic hearing loss cases. Expert review upgraded the GJB6-Clouston syndrome association to Definitive. In summary, GJB6 is definitively associated with autosomal dominant Clouston syndrome. This classification was approved by the ClinGen Hearing Loss Working Group on 4/17/18.