Gene Validity Curation

CFL2 - nemaline myopathy 7

Gene: CFL2 (HGNC:1875)
Classification - 11/25/2019
Disease: nemaline myopathy 7 (MONDO_0012538)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Congenital Myopathies
Evidence Summary: CFL2 was first reported in relation to autosomal recessive nemaline myopathy 7 in 2007 (Agrawal PB, et al., 2007, PMID: 17160903). At least 9 unique variants (e.g. missense, nonsense, and frameshift) 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 7 probands in six publications (PMIDs: 17160903, 22560515, 29457652, 24610938, 27848944, 27447704). Variants in this gene segregated with disease in 3 additional family members. This gene-disease relationship is supported by its biochemical function in actin-filament dynamics (PMID: 26996939), its expression in skeletal muscle (PMID: 11422377), and at least two knockout mouse models (PMIDs: 22343409, 2459838). In summary, there is strong evidence to support the relationship between CFL2 and autosomal recessive nemaline myopathy 7.
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
5.5
7.1
Ong RW et al. 2014 Sep (PMID:24610938); Trujillano D et al. 2017 Feb (PMID:27848944); Fattori F et al. 2018 Jun (PMID:29457652);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
1.6
Agrawal PB et al. 2007 Jan (PMID:17160903); Ockeloen CW et al. 2012 Jul (PMID:22560515); Fattori F et al. 2018 Jun (PMID:29457652);
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) 7.1
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
0.5
1
Chin SM et al. 2016 Apr 24 (PMID:26996939);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Thirion C et al. 2001 Jun (PMID:11422377);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 4 4
Agrawal PB et al. 2012 May 15 (PMID:22343409); Gurniak CB et al. 2014 May-Jun (PMID:24598388);
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) 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 7.1 5 12.1 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
11/25/2019
EXPERT CURATION (DATE)
Definitive
11/25/2019
EVIDENCE SUMMARY
CFL2 was first reported in relation to autosomal recessive nemaline myopathy 7 in 2007 (Agrawal PB, et al., 2007, PMID: 17160903). At least 9 unique variants (e.g. missense, nonsense, and frameshift) 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 7 probands in six publications (PMIDs: 17160903, 22560515, 29457652, 24610938, 27848944, 27447704). Variants in this gene segregated with disease in 3 additional family members. This gene-disease relationship is supported by its biochemical function in actin-filament dynamics (PMID: 26996939), its expression in skeletal muscle (PMID: 11422377), and at least two knockout mouse models (PMIDs: 22343409, 2459838). In summary, there is strong evidence to support the relationship between CFL2 and autosomal recessive nemaline myopathy 7.