Gene Validity Curation

DNM2 - autosomal dominant centronuclear myopathy

Gene: DNM2 (HGNC:2974)
Classification - 12/20/2019
Disease: autosomal dominant centronuclear myopathy (MONDO_0008048)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Congenital Myopathies EP
Evidence Summary: DNM2 was first reported in relation to autosomal dominant centronuclear myopathy in 2005 (Bitoun et al., 16227997). At least ten variants (e.g. missense, in-frame indel, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, experimental data. Variants in this gene have been reported in at least 17 probands in three publications (PMID: 17932957, 16227997, 26273216). Variants in this gene segregated with disease in 24 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. The mechanism for disease is heterozygous gain of function, with CNM DNM2 mutations interrupting the normal regulatory pathway and causing overexpression of DNM2 in the skeletal muscle resulting in myopathy phenotypes. Of note, this gene has also been implicated in Charcot-Marie-Tooth disease, dominant intermediate B and Lethal congenital contracture syndrome 5. These will be assessed separately. This gene-disease association is also supported by shared biochemical function with BIN1, another gene responsible for centronuclear myopathy apparently via DNM2 dysregulation as shown by mouse models. Skin fibroblasts in DNM2 patients also demonstrate modified endocytosis, another factor which can influence the progress of various myopathies. A mouse model displaying the most common CNM variant, R465W, clearly recapitulates the phenotypes observed in human probands. Lastly, expression of siRNAs to block expression of the variant in these same mice fully rescues the disease phenotype. In summary, DNM2 is definitively associated with autosomal dominant centronuclear myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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 7
14
12
Bitoun M et al. 2005 Nov (PMID:16227997); Bitoun M et al. 2007 Dec (PMID:17932957); Abath Neto O et al. 2015 May (PMID:26273216);
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
2.2
2.2
Bitoun M et al. 2005 Nov (PMID:16227997); Bitoun M et al. 2007 Dec (PMID:17932957);
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 6.2 1
Bitoun M et al. 2005 Nov (PMID:16227997);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 6.2    
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) 12
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
1
1
Zhao M et al. 2019 Nov 6. (PMID:31691805);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
1
1
Trochet D et al. 2018 Feb (PMID:29246969);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 3 4
Cowling BS et al. 2011 May (PMID:21514436);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Trochet D et al. 2018 Feb (PMID:29246969);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6

 


 

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 12 6 18 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
12/16/2019
EXPERT CURATION (DATE)
Definitive
12/20/2019
EVIDENCE SUMMARY
DNM2 was first reported in relation to autosomal dominant centronuclear myopathy in 2005 (Bitoun et al., 16227997). At least ten variants (e.g. missense, in-frame indel, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, experimental data. Variants in this gene have been reported in at least 17 probands in three publications (PMID: 17932957, 16227997, 26273216). Variants in this gene segregated with disease in 24 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. The mechanism for disease is heterozygous gain of function, with CNM DNM2 mutations interrupting the normal regulatory pathway and causing overexpression of DNM2 in the skeletal muscle resulting in myopathy phenotypes. Of note, this gene has also been implicated in Charcot-Marie-Tooth disease, dominant intermediate B and Lethal congenital contracture syndrome 5. These will be assessed separately. This gene-disease association is also supported by shared biochemical function with BIN1, another gene responsible for centronuclear myopathy apparently via DNM2 dysregulation as shown by mouse models. Skin fibroblasts in DNM2 patients also demonstrate modified endocytosis, another factor which can influence the progress of various myopathies. A mouse model displaying the most common CNM variant, R465W, clearly recapitulates the phenotypes observed in human probands. Lastly, expression of siRNAs to block expression of the variant in these same mice fully rescues the disease phenotype. In summary, DNM2 is definitively associated with autosomal dominant centronuclear myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.