Gene Validity Classification Summary

Gene/Disease Pair:

RDX : nonsyndromic genetic deafness

HGNC:9944 | MONDO_0019497
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
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
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 5
10
10.5
Khan SY et al. 2007 May (PMID:17226784); Shearer AE et al. 2009 Mar (PMID:19215054); Lee K et al. 2011 Nov 1 (PMID:22567349); Bademci G et al. 2016 Apr (PMID:26226137);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
0.5
Khan SY et al. 2007 May (PMID:17226784);
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 12.35 3
Khan SY et al. 2007 May (PMID:17226784); Shearer AE et al. 2009 Mar (PMID:19215054); Lee K et al. 2011 Nov 1 (PMID:22567349);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 12.35    
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) 12
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 2 1
Shin JB et al. 2013 Mar (PMID:23334578); Salles FT et al. 2014 Jan (PMID:24285636);
Expression 0.5 0 - 2 3 1.5
Khan SY et al. 2007 May (PMID:17226784); Kitajiri S et al. 2004 Aug 16 (PMID:15314067); Pataky F et al. 2004 Feb 24 (PMID:14983055);
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 2 2
Kitajiri S et al. 2004 Aug 16 (PMID:15314067);
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) 4

 


 

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 12 4 16 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
10/04/2018
EXPERT CURATION (DATE)
Definitive
01/02/2018
EVIDENCE SUMMARY
The RDX​ gene has been associated with autosomal recessive nonsndromic hearing loss using the ClinGen Clinical Validity Framework as of 7/14/2017​. This association was made using case-level data only. At least 7 missense, frameshift, nonsense, and splice-site variants have been reported in humans. RDX​ was first associated with this disease in humans as early as 2007​ (Khan et al.​). Association is seen in at least 6​ probands in 4​ publications (17226784, 19215054, 22567349, 26226137), as well as one unpublished case at the Laboratory for Molecular Medicine. Variants in this gene segregated with disease in 11​ additional family members. This gene-disease association is supported by a null mouse model and relevant expression and protein interaction studies. In summary, RDX​ is definitively associated with autosomal recessive nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 1/2/2018.