Gene Validity Classification Summary

Gene/Disease Pair:

PAX3 : Waardenburg syndrome

HGNC:8617 | MONDO_0018094
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
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 2
4
4
Sun L et al. 2016 Oct 19 (PMID:27759048); Jang MA et al. 2015 May (PMID:25932447);
Proband with predicted or proven null variant 1.5 0-2 10 6 8 8
Hol FA et al. 1995 Jan (PMID:7897628); Chen D et al. 2017 Jun 29 (PMID:28690861); Sun L et al. 2016 Oct 19 (PMID:27759048); Choi EY et al. 2018 Oct 11 (PMID:30314436);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 1
0.5
0.5
Sun L et al. 2016 Oct 19 (PMID:27759048);
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 0 0  
Candidate gene sequencing 1.51 1
Hol FA et al. 1995 Jan (PMID:7897628);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 1.51    
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
1.5
2
Kubic JD et al. 2008 Dec (PMID:18983540);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Lang D et al. 2005 Feb 24 (PMID:15729346);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 4 5 4
Ohnishi T et al. 2017 Apr 05 (PMID:28043919); Ohno T et al. 2017 Aug 05 (PMID:28381738); Guo XL et al. 2010 Apr (PMID:20095975);
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
12/04/2018
EXPERT CURATION (DATE)
Definitive
11/15/2017
EVIDENCE SUMMARY
The relationship between PAX3 and autosomal dominant Waardenburg syndrome was evaluated using the ClinGen Clinical Validity Framework as of 10/10/2017. Variants in PAX3 were first reported in humans with this disease as early as 1995 (Hol et al., PMID 7897628). At least 10 unique variants (e.g. missense, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, biochemical function studies and expression in mouse hair follicles as well as several mouse models (PMID: 18983540, 20095975, 28381738, 28043919, 15729346). Variants in this gene have been reported in at least 8 probands in 12 publications (PMIDs 27759048, 7897628, 28690861, 30314436, 25932447). Variants in this gene segregated with disease in 7 additional family members. In summary, PAX3 is definitively associated with autosomal dominant Waardenberg syndrome. 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 11/15/2017 (SOP Version 5).