Gene Validity Classification Summary

Gene/Disease Pair:

MITF : Waardenburg syndrome type 2

HGNC:7105 | MONDO_0019517
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hearing Loss EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
1.5
1.5
Wildhardt G et al. 2013 Mar 18 (PMID:23512835);
Proband with predicted or proven null variant 1.5 0-2 10 10.5 10
Tassabehji M et al. 1994 Nov (PMID:7874167); Wildhardt G et al. 2013 Mar 18 (PMID:23512835); Sun L et al. 2016 Oct 19 (PMID:27759048); Sun J et al. 2017 Jul (PMID:28356565);
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 Evidence of segregation in one or more families   Sequencing Method 0-3 3
 
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total 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) 11.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
2
2
Sun J et al. 2017 Jul (PMID:28356565); Grill C et al. 2013 Nov 1 (PMID:23787126); Tachibana M et al. 1996 Sep (PMID:8782819);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 8 4
Hodgkinson CA et al. 1998 Apr (PMID:9499424); Steingrímsson E et al. 1994 Nov (PMID:7874168); Chen L et al. 2016 Jun 27 (PMID:27349893);
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 11.5 6 17.5 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
07/26/2018
EXPERT CURATION (DATE)
Definitive
07/26/2018
EVIDENCE SUMMARY
The MITF gene has been associated with autosomal dominant Waardenburg syndrome type 2 using the ClinGen Clinical Validity Framework as of 6/14/2017. This association was made using case-level data only. At least 8 variants (missense, in-frame indel, nonsense, stoploss, frameshift, splice, and large deletion) have been reported in humans. MITF was first associated with this disease in humans as early as 1994 (Tassabehji et al.). Association is seen in at least 8 probands in 4 publications (7874167, 23512835, 27759048, 28356565). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. The mechanism for disease is likely haploinsufficiency. This gene-disease association is supported by numerous animal models (Steingrimsson 1994, Hodgkinson 1998, Chen 2016), as well as biochemical functional assays (Grill 2013, Sun 2017). In summary, MITF is definitively associated with autosomal dominant Waardenburg syndrome type 2. 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.