Gene Validity Curation

MAP3K20 - myopathy, centronuclear, 6, with fiber-type disproportion

Gene: MAP3K20 (HGNC:17797)
Classification - 06/08/2020
Disease: myopathy, centronuclear, 6, with fiber-type disproportion (MONDO_0054695)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Congenital Myopathies
Evidence Summary: MAP3K20 was first reported in relation to ​autosomal recessive centronuclear myopathy with fiber-type disproportion ​in ​2017 (Vasli et al., PMID 27816943)​​. At least three unique truncating variants identified by exome sequencing have been reported in humans in three consanguineous families. Evidence ​supporting this gene-disease relationship includes ​case-level genetic evidence suggesting loss of MAP3K20, as well as expression studies suggesting enhanced protein expression in affected tissues. In summary, at present there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. ​
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 3
6
6
Vasli N et al. 2017 Jan (PMID:27816943);
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) 6
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
Vasli N et al. 2017 Jan (PMID:27816943);
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 0 0
Spielmann M et al. 2016 Feb (PMID:26755636);
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 6 0.5 6.5 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)
Moderate
06/08/2020
EXPERT CURATION (DATE)
Moderate
06/08/2020
EVIDENCE SUMMARY
MAP3K20 was first reported in relation to ​autosomal recessive centronuclear myopathy with fiber-type disproportion ​in ​2017 (Vasli et al., PMID 27816943)​​. At least three unique truncating variants identified by exome sequencing have been reported in humans in three consanguineous families. Evidence ​supporting this gene-disease relationship includes ​case-level genetic evidence suggesting loss of MAP3K20, as well as expression studies suggesting enhanced protein expression in affected tissues. In summary, at present there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. ​