Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

P2RX2 : nonsyndromic genetic deafness

HGNC:15459 | MONDO_0019497
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
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 2
Yan D et al. 2013 Feb 5 (PMID:23345450); Faletra F et al. 2014 Jan 25 (PMID:24211385);
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 3 3  
Candidate gene sequencing 3.31 1
Faletra F et al. 2014 Jan 25 (PMID:24211385);
Exome/genome or all genes sequenced in linkage region 13.3 1
Yan D et al. 2013 Feb 5 (PMID:23345450);
Total Summed LOD Score 16.61    
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) 4.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
Yu N et al. 2008 Nov (PMID:18491132);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Yan D et al. 2013 Feb 5 (PMID:23345450);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 1.5 1.5
Yan D et al. 2013 Feb 5 (PMID:23345450); Housley GD et al. 2013 Apr 30 (PMID:23592720);
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) 2.5



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 4.5 2.5 7 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The P2RX2 gene has been associated with autosomal dominant sensorineural hearing loss in three families (Yan 2013, Faletra 2013). The hearing loss in these families had a postlingual onset, was progressive, and co-occurred with tinnitus in one family. Two unique missense variants have been reported, and variants in this gene segregated with disease in >30 additional family members (23345450, 24211385). An additional family was reported in which hearing loss co-occurred with a mitochondrial disorder, however there wasn't strong evidence in support of pathogenicity of the P2RX2 variant for this phenotype and the variant was present in gnomAD. Functional evidence suggests a dominant negative mechanism (Yan et al. 2013). Substantial experimental evidence suggests that the P2RX2 receptor modulates a temporary threshold shift that protects the cochlea from overstimulation by loud noise exposure (Housley et al. 2013). Loss of the P2RX2 receptor in mice increases susceptibility to noise-induced hearing loss, and a significant correlation was found in a large Chinese family between noise exposure during adolescence and severity of hearing loss (Yan et al. 2013). In summary, there is strong evidence to support the association between P2RX2 and autosomal dominant sensorineural hearing loss. Additional reports in humans are needed to reach a definitive classification. This classification was approved by the ClinGen Hearing Loss Working Group on 2/20/18.