Gene Validity Classification Summary

Gene/Disease Pair:

MYO1A : nonsyndromic genetic deafness

HGNC:7595 | MONDO_0019497
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
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 4
0.5
0.5
Donaudy F et al. 2003 Jun (PMID:12736868); Kwon TJ et al. 2014 Jul (PMID:25080041);
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) 0.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Donaudy F et al. 2003 Jun (PMID:12736868);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
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) 0.5

 


 

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 0.5 0.5 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)*
YES
Donaudy F et al. 2003 Jun (PMID:12736868); Eisenberger T et al. 2014 May (PMID:24616153); Tyska MJ et al. 2005 May (PMID:15758024);
CALCULATED CLASSIFICATION (DATE)
Limited
10/03/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Refuted
10/03/2018
REASON(S) FOR CHANGE
24616153; Eisenberger 2014 Identified one heterozygous nonsense variant in MYO1A in a 4-y/o with congenital profound HL- did not segregate with HL in family, girl was found to have homozygous missense MYO7A variants, diagnosed with probable pre-RP Usher. A second congenitally deaf patient from consanguineous family found to have heterozygous nonsense MYO1A variant. Again, alternate cause was found- homozygosity for previously reported missense variant in CIB2. Finally, a third case with one of the variants reported in Donaudy (p.G662E) had several nonsegregations (two hearing as well as one hearing-impaired family members carried variant). Paper noted that four out of eight Donaudy 2003 variants are present in dbSNP/ESP. 27759032; Patton 2017 identified 12 individuals with MYO1A variants (either reported in Donaudy 2003 or predicted LOF) by WES. None had hearing loss outside that expected for age. There was no association between hearing loss and presence of MYO1A variants.
EXPERT CURATION (DATE)
Refuted
01/16/2018
EVIDENCE SUMMARY
The MYO1A gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 3/14/17. This association was made using case-level and case-control data. At least 11 variants (missense, in-frame indel, nonsense, frameshift) have been reported in humans. MYO1A was first associated with this disease in humans as early as 2003 (Donaudy et al.). Of the 11 published variants, one is supported by a functional study, and 10 are refuted by high frequency in gnomAD, nonsegregation with disease, or confirmed alternate cause of disease. A knock-out mouse model does not replicate the hearing loss phenotype. In summary, there is convincing evidence refuting the association between MYO1A and autosomal dominant nonsyndromic hearing loss, which significantly outweighs the evidence supporting the association. This classification was approved by the ClinGen Hearing Loss Working Group on 1/16/18.