Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

MYO7A : nonsyndromic genetic deafness

HGNC:7606 | MONDO_0019497
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 1
2
2
Kaneko Y et al. 2017 Sep (PMID:28802369);
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 10
6
6
Liu XZ et al. 1997 Nov (PMID:9354784); Bolz H et al. 2004 Sep (PMID:15300860); Street VA et al. 2004 May (PMID:15121790); Luijendijk MW et al. 2004 Jul (PMID:15221449); Di Leva F et al. 2006 Jan 9 (PMID:16449806); Sun Y et al. 2011 Jan (PMID:21150918); Wu CC et al. 2013 Feb 22 (PMID:23451214); Sang Q et al. 2013 Jan 29 (PMID:23383098); Li L et al. 2018 May (PMID:29400105);
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 1.5 1.5  
Candidate gene sequencing 24.47 7
Liu XZ et al. 1997 Nov (PMID:9354784); Bolz H et al. 2004 Sep (PMID:15300860); Street VA et al. 2004 May (PMID:15121790); Luijendijk MW et al. 2004 Jul (PMID:15221449); Di Leva F et al. 2006 Jan 9 (PMID:16449806); Sun Y et al. 2011 Jan (PMID:21150918); Sang Q et al. 2013 Jan 29 (PMID:23383098);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 24.47    
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) 9.5
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
Bolz H et al. 2004 Sep (PMID:15300860);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 3 3
Rhodes CR et al. 2004 Sep (PMID:15389316);
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) 3.5

 


 

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 9.5 3.5 13 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
03/19/2018
EVIDENCE SUMMARY
The MYO7A gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 12/27/17. This association was made using case-level data. At least 8 missense variants and 1 deletion have been reported in humans. MYO7A was first associated with this disease in humans as early as 1997 (Liu et al.​). Association is seen in at least 11 probands in 10 publications (9354784, 15300860, 15121790, 15221449, 16449806, 21150918, 23451214, 23383098, 28802369, 29400105). Variants in this gene segregated with disease in >50 additional family members. This gene-disease association is supported by a heterozygous mouse model, a protein interaction study and a biochemical function study. Of note, this gene has also been implicated in Usher syndrome. This has been​ assessed separately. In summary, MYO7A is definitively associated with autosomal dominant nonsyndromic hearing loss. 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 3/19/18.