Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

KCNJ10 : enlarged vestibular aqueduct syndrome

HGNC:6256 | MONDO_0023069
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hearing Loss
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max 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
0
0
Yang T et al. 2009 May (PMID:19426954);
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 Evidence of segregation in one or more families   Sequencing Method 0-3 3
 
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total 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 Total Counted
Function Biochemical Function 0.5 0 - 2 2
0
0
Singh R et al. 2008 Jan (PMID:17959752);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 0
Yang T et al. 2009 May (PMID:19426954); Wangemann P et al. 2004 Aug 20 (PMID:15320950);
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) 0

 


 

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 0 0 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)
No Classification
09/18/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Disputed
09/18/2018
REASON(S) FOR CHANGE
Disputing the digenic inheritance claim.
EXPERT CURATION (DATE)
Disputed
09/18/2018
EVIDENCE SUMMARY
The KCNJ10 gene has been associated with enlarged vestibular aqueducts, and digenic inheritance with SLC26A4, using the ClinGen Clinical Validity Framework as of 7/7/17. KCNJ10 was first associated with this disease in humans as early as 2009 (Yang et al.​). A heterozygous missense variant has been reported in two probands, who also carry a heterozygous likely pathogenic/pathogenic variant in SLC26A4. No segregation information is available. This gene-disease association claim is supported by functional studies, which are not convincing enough to confirm a digenic inheritance (15320950, 17959752, 19426954). In summary, there is convincing evidence disputing the association between KCNJ10 and enlarged vestibular aqueducts, and digenic inheritance with SLC26A4. More evidence is needed to either support or refute the role KCNJ10 plays in this disease. This classification was approved by the ClinGen Hearing Loss Working Group on 2/20/18.