Gene Validity Curation

KBTBD13 - nemaline myopathy 6

Gene: KBTBD13 (HGNC:37227)
Classification - 06/22/2020
Disease: nemaline myopathy 6 (MONDO_0012237)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Congenital Myopathies EP
Evidence Summary: KBTBD13 was first reported in relation to autosomal dominant nemaline myopathy 6 in 2010 (Sambuughin N, et al., 2010, PMID: 21109227). At least 6 unique variants (all missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 9 probands in 5 publications (PMIDs: 31671076, 21109227, 31828823, 29382405, 30208948). Variants in this gene segregated with disease in 47 additional family members. This gene-disease association is supported by its enhanced expression in skeletal muscle (PMID: 21109227), its role in relaxation of skeletal muscle where it interacts with actin (PMID: 31671076), and a knock-in mouse model which recapitulated human disease (PMID: 31671076). 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 9
3.45
3.45
Sambuughin N et al. 2010 Dec 10 (PMID:21109227); Garibaldi M et al. 2018 Sep 13 (PMID:30208948); Wu L et al. 2018 May (PMID:29382405); de Winter JM et al. 2020 Feb 3 (PMID:31671076); Kang ZX et al. 2020 Feb (PMID:31828823);
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 1.5 1.5  
Candidate gene sequencing 15.05 3
Sambuughin N et al. 2010 Dec 10 (PMID:21109227);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 15.05    
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) 4.95
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
1.5
Protein Interaction 0.5 0 - 2 1 1
de Winter JM et al. 2020 Feb 3 (PMID:31671076);
Expression 0.5 0 - 2 1 0.5
Sambuughin N et al. 2010 Dec 10 (PMID:21109227);
Functional Alteration Patient cells 1 0 - 2 2 1
1.5
2
de Winter JM et al. 2020 Feb 3 (PMID:31671076);
Non-patient cells 0.5 0 - 1 1 0.5
de Winter JM et al. 2020 Feb 3 (PMID:31671076);
Models Non-human model organism 2 0 - 4 4 1 2 2
de Winter JM et al. 2020 Feb 3 (PMID:31671076);
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 4.95 5.5 10.45 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
06/22/2020
EXPERT CURATION (DATE)
Moderate
06/22/2020
EVIDENCE SUMMARY
KBTBD13 was first reported in relation to autosomal dominant nemaline myopathy 6 in 2010 (Sambuughin N, et al., 2010, PMID: 21109227). At least 6 unique variants (all missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 9 probands in 5 publications (PMIDs: 31671076, 21109227, 31828823, 29382405, 30208948). Variants in this gene segregated with disease in 47 additional family members. This gene-disease association is supported by its enhanced expression in skeletal muscle (PMID: 21109227), its role in relaxation of skeletal muscle where it interacts with actin (PMID: 31671076), and a knock-in mouse model which recapitulated human disease (PMID: 31671076). 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.