Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

MYOZ2 : hypertrophic cardiomyopathy

HGNC:1330 | MONDO_0005045
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hypertrophic Cardiomyopathy EP
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
0.5
0.5
Osio A et al. 2007 Mar 30 (PMID:17347475); Posch MG et al. 2008 Jul (PMID:18591919);
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) 0.5
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
Frey N et al. 2000 Dec 19 (PMID:11114196);
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
Ruggiero A et al. 2013 Jan 1 (PMID:22987565);
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) 1.5

 


 

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 1.5 2 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)
Limited
08/01/2018
EXPERT CURATION (DATE)
Limited
08/01/2018
EVIDENCE SUMMARY
The MYOZ2 gene has been associated with hypertrophic cardiomyopathy (HCM) in 5 probands in 3 publications. MYOZ2 was first associated with this disease in humans in 2007 (Osio et al, PMID 17347475). One variant (missense), with experimental evidence to support its pathogenicity, was identified in a patient and was shown to segregate with 5 additional family members (Osio et al, 2007, PMID 17347475). Three additional unique variants with little to no experimental evidence to support their pathogenicity were reported (Osio et al, 2007, PMID 17347475; Posch et al, 2008; PMID 18591919). However, the frequencies of these variants in the ExAC database are consistent with benign variation. Another unique variant (missense) was identified in a proband that also harbored a variant in MYH7 and was excluded as causative (Guo et al, 2017, PMID 28296734). The mechanism for disease is unknown. The gene-disease association is supported by expression data and a mouse model. In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. This classification was approved by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on June 26th, 2017.