Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

POU4F3 : nonsyndromic genetic deafness

HGNC:9220 | 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 5 7.5 7.5
Collin RW et al. 2008 Apr (PMID:18228599); Vahava O et al. 1998 Mar 20 (PMID:9506947); Lee HK et al. 2010 Jun 4 (PMID:20434433); Kitano T et al. 2017 May 17 (PMID:28545070);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 4
2
2
Kim HJ et al. 2013 Nov 18 (PMID:24260153); Yang T et al. 2013 Jun 14 (PMID:23767834); Gao X et al. 2018 Apr 4 (PMID:29850532); Lin YH et al. 2017 Aug 8 (PMID:28790396);
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 6.61 2
Collin RW et al. 2008 Apr (PMID:18228599); Zhang C et al. 2016 Nov 24 (PMID:27999687);
Exome/genome or all genes sequenced in linkage region 8.43 2
Cai XZ et al. 2017 Feb (PMID:27535032); Kim HJ et al. 2013 Nov 18 (PMID:24260153);
Total Summed LOD Score 15.04    
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 1
0.5
2
Hertzano R et al. 2004 Sep 15 (PMID:15254021);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 4 2
Costa A et al. 2015 Dec (PMID:26697340); Ma DB et al. 2014 Apr (PMID:24535414); Yoshimura H et al. 2014 Mar 27 (PMID:24676347); Erkman L et al. 1996 Jun 13 (PMID:8637595);
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 4 4
Hertzano R et al. 2004 Sep 15 (PMID:15254021); Erkman L et al. 1996 Jun 13 (PMID:8637595);
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) 6

 


 

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 6 18 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
11/21/2017
EVIDENCE SUMMARY
The POU4F3 gene has been associated with autosomal dominant nonsyndromic hearing loss DFNA15 in at least 18 probands in 18 publications. Missense, in-frame indel, nonsense, frameshift, large deletion variants have been reported in humans, and variants in this gene segregated with disease in over 60 additional family members. POU4F3 was first associated with this disease in humans in 1998 (Vahava et al.). The hearing loss in DFNA15 individuals is progressive, with a highly variable age of onset between the second and fifth decades of life. The mechanism for disease is likely haploinsufficiency, due to the wide variant spectrum, however mice require only one copy of the functional gene to retain hearing (Erkman 1997, Keithley 1999, Hertzano 2004). This gene-disease association is supported by multiple mouse models, expression studies, and in vitro functional assays. In summary, POU4F3 is definitively associated with autosomal dominant nonsyndromic sensorineural hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 11/21/2017.