Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

SOX10 : Waardenburg syndrome type 4C

HGNC:11190 | MONDO_0013202
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 6
12
12
Pingault V et al. 1998 Feb (PMID:9462749); Morín M et al. 2008 Apr 15 (PMID:18348274); Chen K et al. 2014 Jun (PMID:24735604); Ma J et al. 2016 Jun (PMID:27240497); Fernández RM et al. 2014 Feb (PMID:24311220);
Proband with predicted or proven null variant 1.5 0-2 10 1 1.5 1.5
Pingault V et al. 1998 Feb (PMID:9462749);
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
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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
Potterf SB et al. 2000 Jul (PMID:10982026);
Protein Interaction 0.5 0 - 2 1 0.5
Lang D et al. 2003 Apr 15 (PMID:12668617);
Expression 0.5 0 - 2 1 1
Hao X et al. 2014 Jun 2 (PMID:24887110);
Functional Alteration Patient cells 1 0 - 2 2
1
Non-patient cells 0.5 0 - 1 1 1
Lee M et al. 2000 Dec 1 (PMID:10973953);
Models Non-human model organism 2 0 - 4 4 2 2 2
Southard-Smith EM et al. 1998 Jan (PMID:9425902); Potterf SB et al. 2000 Jul (PMID:10982026);
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

 


 

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 5 17 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
06/19/2018
EVIDENCE SUMMARY
The SOX10 gene has been associated with autosomal dominant Waardenburg syndrome using the ClinGen Clinical Validity Framework as of 8/9/2017. This association was made using case-level data only. At least 8 variants (missense, nonsense, insertions, deletions) have been reported in humans. SOX10 was first associated with this disease in humans as early as 1998 (Pingault et al.). Association is seen in at least 9 probands, 8 of which are de novo, in 6 publications (9462749, 18348274, 27863645, 24735604, 27240497, 24311220). Variants in this gene segregated with disease in 2 additional family members. This gene-disease association is supported by relevant experimental evidence including animal models, expression studies, in vitro functional assays, and protein interactions. In summary, SOX10 is definitively associated with autosomal dominant Waardenburg syndrome. This classification was approved by the ClinGen Hearing Loss Working Group on 6/19/2018.