Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

MYH14 : nonsyndromic genetic deafness

HGNC:23212 | 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 2
1.5
1.5
Donaudy F et al. 2004 Apr (PMID:15015131); Kim NK et al. 2015 Nov (PMID:25719458);
Proband with predicted or proven null variant 1.5 0-2 10 2 3 3
Donaudy F et al. 2004 Apr (PMID:15015131); Kim BJ et al. 2017 Apr (PMID:28221712);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 5
2.25
2.25
Donaudy F et al. 2004 Apr (PMID:15015131); Yang T et al. 2005 Nov 15 (PMID:16222661); Kim SJ et al. 2016 Oct 10 (PMID:27393652); Kim BJ et al. 2017 Apr (PMID:28221712);
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 1.8 1.8  
Candidate gene sequencing 5.72 3
Donaudy F et al. 2004 Apr (PMID:15015131); Yang T et al. 2005 Nov 15 (PMID:16222661); Kim BJ et al. 2017 Apr (PMID:28221712);
Exome/genome or all genes sequenced in linkage region 1.2 1
Qing J et al. 2014 Oct 07 (PMID:25289672);
Total Summed LOD Score 6.92    
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 4
0
0
Konings A et al. 2009 Mar (PMID:19183343);
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 8.55
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
1.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1.5
Donaudy F et al. 2004 Apr (PMID:15015131); Fu X et al. 2016 Dec 22 (PMID:28101381);
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 1 1
Fu X et al. 2016 Dec 22 (PMID:28101381);
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) 2.5

 


 

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 8.55 2.5 11.05 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
12/06/2018
EXPERT CURATION (DATE)
Definitive
06/19/2018
EVIDENCE SUMMARY
The relationship between MYH14 and autosomal dominant nonsyndromic genetic deafness was evaluated using the ClinGen Clinical Validity Framework as of 11/10/2017. Variants in MYH14 were first reported in humans with this disease as early as 2004 (Donaudy et al., PMID 15015131). At least 11 unique variants (missense, nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, case-control data, segregation data, and experimental data. Variants in this gene have been reported in at least 9 probands in 10 publications (PMID: 15015131, 16222661, 27393652, 28221712, 25719458, 25289672). Variants in this gene segregated with disease in 25 additional family members. The mechanism for disease is thought to be that MYH14 plays a beneficial role in the protection of the cochlea after acoustic over-stimulation and that loss of function leads to progressive hearing loss (PMID: 28101381).This gene-disease association is supported by animal models and expression studies. In summary, MYH14 is definitively associated with ADNSHL (PMID: 15015131, 28101381). 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 6/19/2018. Note: this gene has also been associated with a neuropathy phenotype that includes hearing loss, but that evidence was not included in this curation.