Gene Validity Classification Summary

Gene/Disease Pair:

MYO3A : nonsyndromic genetic deafness

HGNC:7601 | MONDO_0019497
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
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
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 2
3
3.25
Walsh T et al. 2002 May 28 (PMID:12032315); Choi BY et al. 2013 Aug 22 (PMID:23990876);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
0.25
Qu R et al. 2016 May (PMID:27063751);
Segregation Evidence   Summed LOD Family Count 3 3  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 11.23 1
Walsh T et al. 2002 May 28 (PMID:12032315);
Total Summed LOD Score 11.23    
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) 6.25
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
Walsh T et al. 2002 May 28 (PMID:12032315);
Functional Alteration Patient cells 1 0 - 2 2
1
Non-patient cells 0.5 0 - 1 2 1
Walsh VL et al. 2011 Apr (PMID:21165622); Lelli A et al. 2016 Jan 18 (PMID:26754646);
Models Non-human model organism 2 0 - 4 4 2 5 4
Walsh VL et al. 2011 Apr (PMID:21165622); Lelli A et al. 2016 Jan 18 (PMID:26754646);
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) 5.5

 


 

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 6.25 5.5 11.75 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
CALCULATED CLASSIFICATION (DATE)
Strong
11/27/2018
EXPERT CURATION (DATE)
Strong
11/15/2017
EVIDENCE SUMMARY
The relationship between MYO3A and autosomal recessive nonsyndromic hearing loss was evaluated using the ClinGen Clinical Validity Framework as of 11/14/2017. Variants in MYO3A were first reported in humans with this disease as early as 2002 (Walsh et al.). At least 4 variants (missense, frameshift, nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in in at least 3 probands in 3 publications (12032315, 23990876, 27063751). Variants in this gene segregated with disease in 19 additional family members. A knock-out and a homozygous LOF mouse model have both provided significant evidence for the gene-disease relationship. In summary, there is strong evidence to support the association between MYO3A and autosomal recessive nonsyndromic hearing loss. Additional reports in humans are needed to reach a definitive classification. This classification was approved by the ClinGen Hearing Loss Working Group on 11/15/2017.