Gene Validity Curation

KLHL40 - nemaline myopathy 8

Gene: KLHL40 (HGNC:30372)
Classification - 11/05/2019
Disease: nemaline myopathy 8 (MONDO_0014138)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Congenital Myopathies EP
Evidence Summary: KLHL40 was first reported in relation to autosomal recessive nemaline myopathy 8 in 2013 (Ravenscroft G, et al., PMID: 23746549). At least 26 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, etc) 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 17 probands in 4 publications (PMIDs: 23746549, 26754003, 28973083, 27528495). Variants in this gene segregated with disease in 5 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. This gene-disease association is supported by its exclusive expression in skeletal muscle which is altered in patients, its biochemical function in stabilization of LMOD3 and protein interaction with NEB, as well as zebrafish and mouse models which recapitulate disruption of muscle structures and loss of movement, and a rescue of the mouse model with muscle-specific wild type KLHL40. In summary, KLHL40 is definitively associated with autosomal recessive nemaline myopathy 8. 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
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 7
11
12
Ravenscroft G et al. 2013 Jul 11 (PMID:23746549); Natera-de Benito D et al. 2016 Mar (PMID:26754003); Meng L et al. 2017 Dec 4 (PMID:28973083);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 10
6
Ravenscroft G et al. 2013 Jul 11 (PMID:23746549); Seferian AM et al. 2016 Oct (PMID:27528495);
Segregation Evidence   Summed LOD Family Count 0 0  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 1.45 1
Ravenscroft G et al. 2013 Jul 11 (PMID:23746549);
Total Summed LOD Score 1.45    
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
2
Garg A et al. 2014 Aug (PMID:24960163);
Protein Interaction 0.5 0 - 2 1 0.5
Garg A et al. 2014 Aug (PMID:24960163);
Expression 0.5 0 - 2 1 1
Ravenscroft G et al. 2013 Jul 11 (PMID:23746549);
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
Ravenscroft G et al. 2013 Jul 11 (PMID:23746549); Garg A et al. 2014 Aug (PMID:24960163);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Garg A et al. 2014 Aug (PMID:24960163);
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
08/06/2019
EXPERT CURATION (DATE)
Definitive
11/05/2019
EVIDENCE SUMMARY
KLHL40 was first reported in relation to autosomal recessive nemaline myopathy 8 in 2013 (Ravenscroft G, et al., PMID: 23746549). At least 26 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, etc) 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 17 probands in 4 publications (PMIDs: 23746549, 26754003, 28973083, 27528495). Variants in this gene segregated with disease in 5 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. This gene-disease association is supported by its exclusive expression in skeletal muscle which is altered in patients, its biochemical function in stabilization of LMOD3 and protein interaction with NEB, as well as zebrafish and mouse models which recapitulate disruption of muscle structures and loss of movement, and a rescue of the mouse model with muscle-specific wild type KLHL40. In summary, KLHL40 is definitively associated with autosomal recessive nemaline myopathy 8. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.