Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

ACAD8 : isobutyryl-CoA dehydrogenase deficiency

HGNC:87 | MONDO_0012648
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
Lin Y et al. 2018 Dec (PMID:30253142); Pedersen CB et al. 2006 Sep (PMID:16857760); Sass JO et al. 2004 (PMID:15505379);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 21
Oglesbee D et al. 2007 Feb (PMID:17304052); Nguyen TV et al. 2002 Sep-Oct (PMID:12359132); Lin Y et al. 2018 Dec (PMID:30253142); Santra S et al. 2017 Mar (PMID:28053874); Yun JW et al. 2015 Feb (PMID:24635911); Pedersen CB et al. 2006 Sep (PMID:16857760); Sass JO et al. 2004 (PMID:15505379);
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) 11.75
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
Nguyen TV et al. 2002 Sep-Oct (PMID:12359132);
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 1 2 2
Sabbagha NG et al. 2011 Jul (PMID:21659959);
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) 2.5



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 11.75 2.5 14.25 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between ACAD8 and isobutyryl-CoA dehydrogenase deficiency (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of April, 2019. ACAD8 encodes isobutyryl-CoA dehydrogenase (IBD), which catalyzes the third step of the degradation of valine. Many patients with IBD deficiency are asymptomatic and are identified through newborn screening programs with elevated C4 acylcarnitine concentrations followed by confirmation of isobutyryl-CoA dehydrogenase activity. Variants in ACAD8 were first reported in humans with this deficiency in 2002 (Nguyen et al., PMID 12359132; Roe et al., 1998; PMID 9889013). At least 27 unique variants (missense, nonsense, frameshift, splicing, deletion) have been identified in humans from at least 9 publications. Evidence supporting this gene-disease relationship includes case-level and experimental data. This gene-disease relationship is supported by biochemical assays and a mouse model. In summary, ACAD8 is definitively associated with autosomal recessive isobutyryl-CoA dehydrogenase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on 4/26/19 (SOP Version 5).