Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

ACADSB : 2-methylbutyryl-CoA dehydrogenase deficiency

HGNC:91 | MONDO_0012392
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Aminoacidopathy
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

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
6
12
Alfardan J et al. 2010 Aug (PMID:20547083);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 12
8.5
Andresen BS et al. 2000 Nov (PMID:11013134); Sass JO et al. 2008 Jan (PMID:17945527); Matern D et al. 2003 Jul (PMID:12837870); Alfardan J et al. 2010 Aug (PMID:20547083); Madsen PP et al. 2006 Feb (PMID:16317551); Kanavin OJ et al. 2007 Sep 20 (PMID:17883863);
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
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4
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) 0

 


 

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 0 12 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
03/26/2019
EXPERT CURATION (DATE)
Definitive
03/22/2019
EVIDENCE SUMMARY
The relationship between ACADSB and 2-methylbutyryl-CoA dehydrogenase deficiency (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of March 12, 2019. Variants in ACADSB were first reported in humans with this deficiency as early as 2000 (Gibson, PMID: 10832746; Andresen, PMID: 11013134). The clinical significance of this disease is uncertain because almost 90% of patients are asymptomatic (Porta, 2019, PMID: 30730842). At least 15 variants have been reported in the literature (missense, nonsense, splicing). In summary, ACADSB is definitively associated with autosomal recessive 2-methylbutyryl-CoA dehydrogenase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on March 22nd, 2019.