Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

POU3F4 : nonsyndromic genetic deafness

HGNC:9217 | MONDO_0019497
Mode of Inheritance: X-linked inheritance (HP:0001417)
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 2
4
4
Bitner-Glindzicz M et al. 1995 Aug (PMID:7581392); Pollak A et al. 2016 Dec 12 (PMID:27941975);
Proband with predicted or proven null variant 1.5 0-2 10 7 10.5 10
de Kok YJ et al. 1995 Feb 03 (PMID:7839145); Bitner-Glindzicz M et al. 1995 Aug (PMID:7581392); Pollak A et al. 2016 Dec 12 (PMID:27941975);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 1
0.5
0.5
de Kok YJ et al. 1995 Feb 03 (PMID:7839145);
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 1 1  
Candidate gene sequencing 3.01 1
de Kok YJ et al. 1995 Feb 03 (PMID:7839145);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 3.01    
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
1.5
Protein Interaction 0.5 0 - 2 2 1
Raft S et al. 2014 Oct 09 (PMID:25299585); Kidokoro Y et al. 2014 Sep 26 (PMID:25259580);
Expression 0.5 0 - 2 1 0.5
Raft S et al. 2014 Oct 09 (PMID:25299585);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Parzefall T et al. 2013 Aug (PMID:23606368);
Models Non-human model organism 2 0 - 4 4 2 4 4
Phippard D et al. 2000 Jan 01 (PMID:10587581); Phippard D et al. 1999 Jul 15 (PMID:10407036);
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
01/05/2018
EVIDENCE SUMMARY
The POU3F4 gene has been associated with X-linked nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 9/25/2017. This association was made using case-level data only. At least 10 missense, frameshift, nonsense variants have been reported in humans. POU3F4 was first associated with this disease in humans as early as 1995 (de Kok et al.). Association is seen in at least 10 probands in 3 publications (7839145, 7581392, 27941975). Variants in this gene segregated with disease in 6 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. This gene-disease association is supported by a spontaneous mouse model and a null mouse model, both with hearing loss, as well as other relevant expression and protein interaction studies. In summary, POU3F4 is definitively associated with X-linked nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 1/5/2018.