ACADL

protein-coding

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

Gene summary

The protein encoded by this gene belongs to the acyl-CoA dehydrogenase family, which is a family of mitochondrial flavoenzymes involved in fatty acid and branched chain amino-acid metabolism. This protein is one of the four enzymes that catalyze the initial step of mitochondrial beta-oxidation of straight-chain fatty acid. Defects in this gene are the cause of long-chain acyl-CoA dehydrogenase (LCAD) deficiency, leading to nonketotic hypoglycemia. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001608.4

Inheritance

ClinVar variants

U:66B:21

Top phenotype

ACADL-related disorder

gnomAD constraint

pLI —, LoF o/e 0.81

Max pathogenic AF

—

Genomic locus

chr2:210,187,126-210,225,447

External References & Databases

Ensembl (ENSG00000115361)

Transcript & Mutation Effects

hg38 • Region Span ~38.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

long chain acyl-CoA dehydrogenase deficiencyNO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0020531

Submitter: ClinGen

ACADL was first reported in relation to autosomal recessive long chain acyl-CoA dehydrogenase deficiency in 1993 (Yamaguchi S, et al., 1993, PMID: 8356011). Initial reports of LCAD deficient patients (PMIDs 1945557 and 4022672) were subsequently found to have a VLCAD deficiency and/or no pathogenic LCAD variants were identified. More recent reports (PMID 24591516) suggest that LCAD deficiency may manifest primarily as pulmonary disease, however the only identified variant remains a common polymorphism (Lys333Gln) for which there is some evidence of a functional impact (PMID 32389575). In summary, there is convincing evidence disputing the relationship between ACADL and autosomal recessive long chain acyl-CoA dehydrogenase deficiency. More evidence is needed to either support or refute the role ACADL plays in this disease. This gene-disease pair was originally evaluated by the FAO GCEP on 09/25/2018. It was reevaluated on 01/15/2021 and 03/07/2024. As a result of this reevaluation, the classification did not change as no new information is contributing to the classification.

hereditary pulmonary alveolar proteinosisLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012580

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACADL variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 78

ACADL-related disorderTotal: 18

not providedTotal: 11

Long chain acyl-CoA dehydrogenase deficiencyTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001608.4. 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				12 clinvar	1 clinvar	13
missense			62 clinvar	6 clinvar		68
nonsense						0
start loss						0
frameshift			1 clinvar	2 clinvar		3
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	66	20	1	87

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001608.4	RefSeq	NP_001599.1	11	MANE Select
ENST00000233710.4	Ensembl	ENSP00000233710.3	11	MANE Select
ENST00000862329.1	Ensembl	ENSP00000532388.1	10	Standard
ENST00000862329.2	Ensembl	ENSP00000532388.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fatty acid degradation - Homo sapiens (human)
PPAR signaling pathway - Homo sapiens (human)
Long chain acyl-CoA dehydrogenase deficiency (LCAD)
Trifunctional protein deficiency
Carnitine palmitoyl transferase deficiency (II)

Biological Process

temperature homeostasis
fatty acid beta-oxidation
carnitine metabolic process, CoA-linked
fatty acid beta-oxidation using acyl-CoA dehydrogenase
carnitine catabolic process

Molecular Function

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

Cellular Component

mitochondrion
mitochondrial matrix
mitochondrial membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000233710
Coding exons: 11
Length: 37553
Individuals with no LoFs: 125577
Homozygous LoFs: 0
Heterozygous LoFs: 170
Defined: 125747
p: 0.000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.856	196	233	0.842	0.0000114	2797
Missense (PolyPhen)		74	81.338	0.90979		1044
Synonymous	1.79	61	81.5	0.748	0.00000418	815
Loss of Function	0.913	21	26.0	0.807	0.00000132	300

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00055	0.00055	rare
Ashkenazi Jewish	0.00060	0.00060	rare
East Asian	0.00038	0.00038	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00081	0.00081	rare
South Asian	0.00085	0.00085	rare
Other	0.0023	0.0023	notable

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.326

Intolerance Scores

LoFtool: 0.344
RVIS EVS: -0.36
RVIS percentile EVS: 29.16

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.296

Gene Damage Prediction

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