Gene Validity Curation

KLHL41 - nemaline myopathy 9

Gene: KLHL41 (HGNC:16905)
Classification - 11/05/2019
Disease: nemaline myopathy 9 (MONDO_0014326)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Congenital Myopathies EP
Evidence Summary: KHLH41 was first reported in relation to autosomal-recessive nemaline myopathy 9 in 2013 (Gupta VA, et al., PMID: 24268659). At least 8 unique variants (e.g. missense, in-frame indel, frameshift, large deletion) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Summary of Case Level Data: 2.8 POINTS. Variants in this gene have been reported in at least 7 probands in 3 publications ( PMID: 24268659, 28939701, 28749478). The mechanism for the disease is homozygous loss of function (PMID: 24268659). This gene-disease association is supported by animal models, expression studies, and in vitro functional assays. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
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 2
2.5
2.8
Gupta VA et al. 2013 Dec 5 (PMID:24268659);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
0.3
Gupta VA et al. 2013 Dec 5 (PMID:24268659); van Diemen CC et al. 2017 Oct (PMID:28939701);
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) 2.8
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
Ramirez-Martinez A et al. 2017 Aug 9 (PMID:28826497);
Protein Interaction 0.5 0 - 2 1 0.5
Ramirez-Martinez A et al. 2017 Aug 9 (PMID:28826497);
Expression 0.5 0 - 2 1 1
Ramirez-Martinez A et al. 2017 Aug 9 (PMID:28826497);
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
Gupta VA et al. 2013 Dec 5 (PMID:24268659); Ramirez-Martinez A et al. 2017 Aug 9 (PMID:28826497);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Gupta VA et al. 2013 Dec 5 (PMID:24268659);
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 2.8 6 8.8 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)
Moderate
11/05/2019
EXPERT CURATION (DATE)
Moderate
11/05/2019
EVIDENCE SUMMARY
KHLH41 was first reported in relation to autosomal-recessive nemaline myopathy 9 in 2013 (Gupta VA, et al., PMID: 24268659). At least 8 unique variants (e.g. missense, in-frame indel, frameshift, large deletion) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Summary of Case Level Data: 2.8 POINTS. Variants in this gene have been reported in at least 7 probands in 3 publications ( PMID: 24268659, 28939701, 28749478). The mechanism for the disease is homozygous loss of function (PMID: 24268659). This gene-disease association is supported by animal models, expression studies, and in vitro functional assays. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.