ACADVL

protein-coding

acyl-CoA dehydrogenase very long chain, the group of Acyl-CoA dehydrogenase family

Gene summary

The protein encoded by this gene is targeted to the inner mitochondrial membrane where it catalyzes the first step of the mitochondrial fatty acid beta-oxidation pathway. This acyl-Coenzyme A dehydrogenase is specific to long-chain and very-long-chain fatty acids. A deficiency in this gene product reduces myocardial fatty acid beta-oxidation and is associated with cardiomyopathy. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000018.4

Inheritance

ClinVar variants

P:590U:568B:412

Top phenotype

Acyl-CoA dehydrogenase, very long chain, deficiency of

gnomAD constraint

pLI —, LoF o/e 0.76

Max pathogenic AF

—

Genomic locus

chr17:7,217,125-7,225,266

External References & Databases

Ensembl (ENSG00000072778)

Transcript & Mutation Effects

hg38 • Region Span ~8.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

very long chain acyl-CoA dehydrogenase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008723

Submitter: PanelApp Australia

very long chain acyl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008723

Submitter: G2P

very long chain acyl-CoA dehydrogenase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008723

Submitter: Labcorp Genetics (formerly Invitae)

very long chain acyl-CoA dehydrogenase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008723

Submitter: Orphanet

very long chain acyl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008723

Submitter: Natera

very long chain acyl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008723

Submitter: ClinGen

Clinical Genomic Database (CGD)

Acyl-CoA dehydrogenase, very long chain, deficiency ofAR

Manifestation: Biochemical; Cardiovascular; Gastrointestinal; Musculoskeletal; Neurologic; Renal

Intervention: Biochemical; Cardiovascular; Musculoskeletal; Renal

Rationale: There are multiple forms of VLCAD deficiency, and interventions depend on the form (typical medical/dietary therapy considerations include IV glucose/carnitine in initial phases, as well as low-fat, diet with MCT oil and carnitine, or triheptanoin, and avoidance of fasting); In the severe, early-onset form, medical treatment of cardiomyopathy may be beneficial; In thechildhood onset form, treatment of hypoketotic hypoglycemia may be beneficial; In the adult-onset, myopathic form, preventive measures related to with irhabdomyolysis, and myoglobinuria after exercise or fasting may be beneficial

Refs: 4022672; 2059253; 2000272; 1527994; 8422439; 8356011; 8145917; 7668252; 7769092; 7479827; 8739959; 8554073; 9709714; 9877038; 9546340; 9973285; 10077518; 10790204; 11158518; 11524729; 15210884; 17636072; 19327992; 19208414; 19399638; 19452263; 21531094; 21814341; 22847164; 23480858; 33610471

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACADVL variants in ClinVar

16 Conditions Cataloged

Very long chain acyl-CoA dehydrogenase deficiencyTotal: 2022

not providedTotal: 292

not specifiedTotal: 193

Inborn genetic diseasesTotal: 123

ACADVL-related disorderTotal: 119

RhabdomyolysisTotal: 4

Abnormality of the musculatureTotal: 3

Acute rhabdomyolysisTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000018.4. 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	1 clinvar	2 clinvar	26 clinvar	394 clinvar	4 clinvar	427
missense	21 clinvar	208 clinvar	516 clinvar	9 clinvar	5 clinvar	759
nonsense	24 clinvar	27 clinvar	3 clinvar			54
start loss			2 clinvar			2
frameshift	75 clinvar	129 clinvar	7 clinvar			211
splice donor/acceptor (+/-2bp)	23 clinvar	80 clinvar	14 clinvar			117
Total	144	446	568	403	9	1570

Highest pathogenic variant AF is 0.0015937401

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 119 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000018.4	RefSeq	NP_000009.1	20	MANE Select
ENST00000356839.10	Ensembl	ENSP00000349297.5	20	MANE Select
NM_001033859.3	RefSeq	NP_001029031.1	19	Standard
NM_001270447.2	RefSeq	NP_001257376.1	21	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
acadvl	Danio rerio	Structure: head Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

acadvl

Danio rerio

Structure: head

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fatty acid degradation - Homo sapiens (human)
Long chain acyl-CoA dehydrogenase deficiency (LCAD)
Trifunctional protein deficiency
Carnitine palmitoyl transferase deficiency (II)
Very-long-chain acyl coa dehydrogenase deficiency (VLCAD)

Biological Process

temperature homeostasis
fatty acid beta-oxidation
response to cold
energy derivation by oxidation of organic compounds
epithelial cell differentiation

Molecular Function

fatty-acyl-CoA binding
acyl-CoA dehydrogenase activity
long-chain-acyl-CoA dehydrogenase activity
very-long-chain-acyl-CoA dehydrogenase activity
flavin adenine dinucleotide binding

Cellular Component

nucleus
nucleolus
mitochondrion
mitochondrial inner membrane
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000543245
Coding exons: 21
Length: 8149
Individuals with no LoFs: 125673
Homozygous LoFs: 0
Heterozygous LoFs: 75
Defined: 125748
p: 0.000298

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.210	390	379	1.03	0.0000227	4385
Missense (PolyPhen)		136	139.4	0.97558		1639
Synonymous	-1.74	171	144	1.18	0.00000864	1383
Loss of Function	1.32	27	35.5	0.761	0.00000186	422

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00062	0.00062	rare
Latino/Admixed American	0.00041	0.00040	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00027	0.00027	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00031	0.00031	rare
South Asian	0.00020	0.00020	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Active toward esters of long-chain and very long chain fatty acids such as palmitoyl-CoA, myristoyl-CoA and stearoyl-CoA. Can accommodate substrate acyl chain lengths as long as 24 carbons, but shows little activity for substrates of less than 12 carbons. {ECO:0000269|PubMed:18227065}.;
Disease: DISEASE: Acyl-CoA dehydrogenase very long-chain deficiency (ACADVLD) [MIM:201475]: An inborn error of mitochondrial fatty acid beta-oxidation which leads to impaired long-chain fatty acid beta-oxidation. It is clinically heterogeneous, with three major phenotypes: a severe childhood form characterized by early onset, high mortality and high incidence of cardiomyopathy; a milder childhood form with later onset, characterized by hypoketotic hypoglycemia, low mortality and rare cardiomyopathy; an adult form, with isolated skeletal muscle involvement, rhabdomyolysis and myoglobinuria, usually triggered by exercise or fasting. {ECO:0000269|PubMed:10077518, ECO:0000269|PubMed:8554073, ECO:0000269|PubMed:9546340}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.286

Intolerance Scores

LoFtool: 0.0621
RVIS EVS: 0.03
RVIS percentile EVS: 55.79

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.802

Gene Damage Prediction

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