ACAD8

protein-coding

acyl-CoA dehydrogenase family member 8, the group of Acyl-CoA dehydrogenase family

Gene summary

This gene encodes a member of the acyl-CoA dehydrogenase family of enzymes that catalyze the dehydrogenation of acyl-CoA derivatives in the metabolism of fatty acids or branch chained amino acids. The encoded protein is a mitochondrial enzyme that functions in catabolism of the branched-chain amino acid valine. Defects in this gene are the cause of isobutyryl-CoA dehydrogenase deficiency.[provided by RefSeq, Nov 2009]

MANE transcript

NM_014384.3

Inheritance

ClinVar variants

P:53U:124B:43

Top phenotype

Isobutyryl-CoA dehydrogenase deficiency

gnomAD constraint

pLI —, LoF o/e 0.89

Max pathogenic AF

—

Genomic locus

chr11:134,253,548-134,265,855

External References & Databases

Ensembl (ENSG00000151498)

Transcript & Mutation Effects

hg38 • Region Span ~12.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

isobutyryl-CoA dehydrogenase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012648

Submitter: Orphanet

isobutyryl-CoA dehydrogenase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012648

Submitter: Labcorp Genetics (formerly Invitae)

isobutyryl-CoA dehydrogenase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012648

Submitter: Ambry Genetics

isobutyryl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012648

Submitter: ClinGen

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).

isobutyryl-CoA dehydrogenase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012648

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Isobutyryl-CoA dehydrogenase deficiencyAR

Manifestation: Biochemical; Cardiovascular; Hematologic; Musculoskeletal; Neurologic

Intervention: Biochemical

Rationale: Metabolic precautions may be beneficial to prevent and treat acute decompensation; Medical treatment (eg, with oral L-carnitine) has been reported as allowing growth catch-up and normalization of cardiac status

Refs: 9889013; 12359132; 17304052; 16857760; 17924841; 21290185; 22241096

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACAD8 variants in ClinVar

6 Conditions Cataloged

Deficiency of isobutyryl-CoA dehydrogenaseTotal: 196

not providedTotal: 79

Inborn genetic diseasesTotal: 48

not specifiedTotal: 13

ACAD8-related disorderTotal: 12

Inborn errors of metabolismTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014384.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			9 clinvar	31 clinvar	1 clinvar	41
missense	5 clinvar	20 clinvar	111 clinvar	10 clinvar	1 clinvar	147
nonsense	7 clinvar	3 clinvar	1 clinvar			11
start loss		4 clinvar				4
frameshift	4 clinvar	1 clinvar	1 clinvar			6
splice donor/acceptor (+/-2bp)	3 clinvar	6 clinvar	2 clinvar			11
Total	19	34	124	41	2	220

Highest pathogenic variant AF is 0.00023606591

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 84 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014384.3	RefSeq	NP_055199.1	11	MANE Select
ENST00000281182.9	Ensembl	ENSP00000281182.5	11	MANE Select
NM_001441136.1	RefSeq	NP_001428065.1	11	Standard
NM_001441137.1	RefSeq	NP_001428066.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Valine, leucine and isoleucine degradation - Homo sapiens (human)
3-Methylglutaconic Aciduria Type I
Valine, Leucine and Isoleucine Degradation
2-Methyl-3-Hydroxybutryl CoA Dehydrogenase Deficiency
Isovaleric Aciduria

Biological Process

valine catabolic process
lipid metabolic process
branched-chain amino acid catabolic process
oxidation-reduction process

Molecular Function

acyl-CoA dehydrogenase activity
flavin adenine dinucleotide binding

Cellular Component

mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000281182
Coding exons: 11
Length: 12361
Individuals with no LoFs: 125678
Homozygous LoFs: 0
Heterozygous LoFs: 70
Defined: 125748
p: 0.000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.222	221	231	0.959	0.0000132	2701
Missense (PolyPhen)		89	93.727	0.94956		1080
Synonymous	-1.95	115	91.3	1.26	0.00000562	823
Loss of Function	0.508	22	24.7	0.890	0.00000156	246

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00044	0.00043	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00035	0.00033	rare
South Asian	0.00033	0.00033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Has very high activity toward isobutyryl-CoA. Is an isobutyryl-CoA dehydrogenase that functions in valine catabolism. Plays a role in transcriptional coactivation within the ARC complex. {ECO:0000269|PubMed:12359132}.;

Recessive Scores

pRec: 0.250

Intolerance Scores

LoFtool: 0.287
RVIS EVS: -0.38
RVIS percentile EVS: 27.88

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.992

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium