Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GRXCR2 : nonsyndromic genetic deafness

HGNC:33862 | MONDO_0019497
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
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 1
2
2
Imtiaz A et al. 2014 May (PMID:24619944);
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 1  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 2.7 1
Imtiaz A et al. 2014 May (PMID:24619944);
Total Summed LOD Score 2.7    
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) 3
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
1.5
Protein Interaction 0.5 0 - 2 1 0.5
Liu C et al. 2018 Oct 30 (PMID:30380417);
Expression 0.5 0 - 2 2 1
Avenarius MR et al. 2018 Aug 29 (PMID:30157177); Liu C et al. 2018 Oct 30 (PMID:30380417);
Functional Alteration Patient cells 1 0 - 2 2
0
Non-patient cells 0.5 0 - 1 1 0
Imtiaz A et al. 2014 May (PMID:24619944);
Models Non-human model organism 2 0 - 4 4 2 5 4
Avenarius MR et al. 2018 Aug 29 (PMID:30157177); Liu C et al. 2018 Oct 30 (PMID:30380417);
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) 5.5

 


 

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 3 5.5 8.5 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)
Moderate
01/23/2019
EXPERT CURATION (DATE)
Moderate
01/07/2019
EVIDENCE SUMMARY
GRXCR2 was first reported in relation to autosomal recessive nonsyndromic hearing loss in 2014 (Imtiaz et al.) At least 1 missense variant has been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. Variants in this gene have been reported in at least 1 proband in 1 publication (PMID 24619944). Variants in this gene segregated with disease in 2 additional family members. This gene-disease association is supported by multiple mouse models, functional alteration studies, protein interaction studies indicating that GRXCR2 interacts with TPRN, and inner ear expression studies (Avenarious et al. 2012, 30157177; Avenarius 2012, a PhD thesis; Liu et al. 2018, 30380417). In summary, there is moderate evidence to support this gene-disease association. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hearing Loss Working Group on 1/7/2019.