Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

MYO1C : autosomal dominant nonsyndromic deafness

HGNC:7597 | MONDO_0019587
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hearing Loss
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
Proband with predicted or proven null variant 1.5 0-2 10
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) 0
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 0.5
Dumont RA et al. 2002 Dec (PMID:12486594);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 0.5
Adamek N et al. 2011 Jan (PMID:20640478);
Models Non-human model organism 2 0 - 4 4
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) 1

 


 

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 0 1 1 NO
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
Zadro C et al. 2009 Jan (PMID:19027848);
CALCULATED CLASSIFICATION (DATE)
Limited
06/28/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Disputed
06/28/2018
REASON(S) FOR CHANGE
This association is disputed because all of the missense variants reported are at high frequency in gnomAD, and the loss of function variants have no evidence of gene impact. The gene is not contrained for LOF variants according to ExAC.
EXPERT CURATION (DATE)
Disputed
06/28/2018
EVIDENCE SUMMARY
The MYO1C gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 6/26/2018. This association was made using case-level data only. Multiple missense variants have been reported in humans by Zadro et al. 2009, however each of these variants is present in high frequency in gnomAD. The loss-of-function variants reported by Ji et al. 2014 have no family history information or functional evidence to prove variant impact. In summary, there is convincing evidence disputing the association between autosomal dominant nonsyndromic hearing loss. More evidence is needed to either support or refute the role MYO1C plays in this disease. This classification was approved by the ClinGen Hearing Loss Working Group on 6/26/2018.