Gene Validity Curation

CCDC78 - centronuclear myopathy

Gene: CCDC78 (HGNC:14153)
Classification - 12/09/2019
Disease: centronuclear myopathy (MONDO_0018947)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Congenital Myopathies EP
Evidence Summary: CCDC78 was reported in relation to autosomal dominant centronuclear myopathy in 2012 (Majczenko et al., PMID: 22818856). At least two unique splicing variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 2 probands in 2 publications (PMID: 22818856, 25635128). This gene-disease association is supported by expression studies and an animal model. In summary, there is limited 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 2 3 3
Majczenko K et al. 2012 Aug 10 (PMID:22818856); Chae JH et al. 2015 Mar (PMID:25635128);
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
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 0 0  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 1.2 1
Majczenko K et al. 2012 Aug 10 (PMID:22818856);
Total Summed LOD Score 1.2    
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) 3
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
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Majczenko K et al. 2012 Aug 10 (PMID:22818856);
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
Majczenko K et al. 2012 Aug 10 (PMID:22818856);
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) 4

 


 

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 3 4 7 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
01/13/2020
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Limited
01/13/2020
REASON(S) FOR CHANGE
Only 2 unrelated probands with mutations in the gene were scored. In order for the gene to be classified as "Moderate" at least 3 unrelated probands need to be scored.
EXPERT CURATION (DATE)
Limited
12/09/2019
EVIDENCE SUMMARY
CCDC78 was reported in relation to autosomal dominant centronuclear myopathy in 2012 (Majczenko et al., PMID: 22818856). At least two unique splicing variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 2 probands in 2 publications (PMID: 22818856, 25635128). This gene-disease association is supported by expression studies and an animal model. In summary, there is limited 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.