Gene Validity Curation

LMOD3 - nemaline myopathy 10

Gene: LMOD3 (HGNC:6649)
Classification - 09/09/2019
Disease: nemaline myopathy 10 (MONDO_0014513)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Congenital Myopathies EP
Evidence Summary: The relationship between LMOD3 and Nemaline Myopathy 10 was evaluated using the ClinGen Clinical Validity Framework as of 07/31/19. Variants in LMOD3 were first reported in humans with this disease in 2014 (Yuen et al., 25250574). At least 17 variants (e.g. missense, in-frame indel, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 12 Points Variants in this gene have been reported in at least 19 probands in 3 publications (28815944, 30291184), most of which are due to loss of function mutations leading to severe phenotypes. Although some of the probands were unable to be counted due to absent parental testing, the genetic evidence far exceeded the maximum available. Slightly more evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease appears to be homozygous loss of function, as demonstrated by KO mouse models and the autosomal recessive inheritance. Summary of Experimental Data: 5.5 Points This gene-disease association is supported by two separate mouse models, each recapitulating the base phenotype of the disorder. There are several other pieces of functional evidence, most notably the interactions with KLHL40, the actin-binding function of the protein, and expression primarily in the muscle. In summary, LMOD3 is definitively associated with Nemaline Myopathy 10. Although the research is relatively recent, the amount and quality of the evidence present is more than enough to demonstrate this association. This classification was approved by the ClinGen Aminoacidopathy Working Group on 09/09/2019.
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 14
17
12
Yuen M et al. 2014 Nov (PMID:25250574); Abbott M et al. 2017 Oct (PMID:28815944);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 5
1.4
Yuen M et al. 2014 Nov (PMID:25250574); Schatz UA et al. 2018 Oct 30 (PMID:30291184);
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) 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
0.5
1.5
Yuen M et al. 2014 Nov (PMID:25250574);
Protein Interaction 0.5 0 - 2 1 0.5
Garg A et al. 2014 Aug (PMID:24960163);
Expression 0.5 0 - 2 1 0.5
Yuen M et al. 2014 Nov (PMID:25250574);
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
Tian L et al. 2015 Jun (PMID:26035871); Cenik BK et al. 2015 Apr (PMID:25774500);
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) 5.5

 


 

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 12 5.5 17.5 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
09/09/2019
EVIDENCE SUMMARY
The relationship between LMOD3 and Nemaline Myopathy 10 was evaluated using the ClinGen Clinical Validity Framework as of 07/31/19. Variants in LMOD3 were first reported in humans with this disease in 2014 (Yuen et al., 25250574). At least 17 variants (e.g. missense, in-frame indel, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 12 Points Variants in this gene have been reported in at least 19 probands in 3 publications (28815944, 30291184), most of which are due to loss of function mutations leading to severe phenotypes. Although some of the probands were unable to be counted due to absent parental testing, the genetic evidence far exceeded the maximum available. Slightly more evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease appears to be homozygous loss of function, as demonstrated by KO mouse models and the autosomal recessive inheritance. Summary of Experimental Data: 5.5 Points This gene-disease association is supported by two separate mouse models, each recapitulating the base phenotype of the disorder. There are several other pieces of functional evidence, most notably the interactions with KLHL40, the actin-binding function of the protein, and expression primarily in the muscle. In summary, LMOD3 is definitively associated with Nemaline Myopathy 10. Although the research is relatively recent, the amount and quality of the evidence present is more than enough to demonstrate this association. This classification was approved by the ClinGen Aminoacidopathy Working Group on 09/09/2019.