rs118204017 — ACADVL

ACADVL missense variant (p.Phe458Leu) classified likely pathogenic for VLCAD deficiency; heterozygous carriers are asymptomatic but important to identify for reproductive counseling

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ACADVL p.Phe458Leu — A Carrier Variant in the Fat-Burning Engine

Your cells run on fat during fasting, prolonged exercise, and sleep. The first step of burning very long-chain fatty acids — chains of 14 to 20 carbons — depends on very long-chain acyl-CoA dehydrogenase (VLCAD)11 very long-chain acyl-CoA dehydrogenase (VLCAD)
encoded by ACADVL on chromosome 17p13; the enzyme catalyzes the alpha,beta-dehydrogenation of fatty acyl-CoA esters in the inner mitochondrial membrane, the enzyme encoded by ACADVL. When both copies of this gene are severely disrupted, VLCAD deficiency (VLCADD) results — a rare inborn error of metabolism that can cause hypertrophic cardiomyopathy in infancy, hypoglycemia during fasting, or exercise-induced muscle breakdown in adults. The rs118204017 variant creates a phenylalanine-to-leucine substitution at residue 458, and has been classified as likely pathogenic22 classified as likely pathogenic
ClinVar VCV000001632; reviewed by the ClinGen ACADVL Variant Curation Expert Panel, 3-star review status, December 2022 by the ClinGen ACADVL Expert Panel. At a population frequency of roughly 1 in 40,000 chromosomes in gnomAD, it is exceptionally rare — meaning most people who carry one copy will never meet a partner who carries the same or another ACADVL variant.

The Mechanism

ACADVL encodes a homodimeric flavoenzyme33 homodimeric flavoenzyme
VLCAD is a 70 kDa subunit homodimer anchored to the inner mitochondrial membrane; it works in concert with the mitochondrial trifunctional protein (MTP) to complete each cycle of fatty acid beta-oxidation that anchors to the inner mitochondrial membrane. Phenylalanine 458 sits within the acyl-CoA substrate binding channel of the mature enzyme. The substitution to leucine changes the shape of this channel, reducing catalytic efficiency for very long-chain substrates. Unlike null variants (frameshifts, nonsense, splice-site mutations) that abolish enzyme production entirely, missense variants like p.Phe458Leu typically preserve partial residual activity — estimated at roughly 20% of normal in one functional study — which is why homozygosity or compound heterozygosity for this variant tends to produce a milder clinical presentation than loss-of-function alleles. In a single heterozygous carrier, the one intact ACADVL copy produces sufficient enzyme for completely normal fatty acid oxidation.

The Evidence

The variant was first identified by Cox et al. in 199844 Cox et al. in 1998
Cox GF et al., J Pediatr 133:247–53 in an infant who presented at 5 months with severe hypertrophic cardiomyopathy, hepatomegaly, encephalopathy, and hypotonia — compound heterozygous for p.Phe458Leu on one allele and a splice site mutation on the other. The cardiomyopathy resolved substantially within one year on a low long-chain fat diet supplemented with medium-chain triglyceride (MCT) oil and carnitine, demonstrating that VLCADD-related cardiomyopathy is treatable when identified early.

The genotype-phenotype landscape was mapped by Andresen et al. 199955 Andresen et al. 1999
PMID 9973285, AJHG 64:479–494 across 55 unrelated patients with all clinical forms of VLCADD. Patients with severe early-onset disease consistently carried null variants on both alleles; those with the milder hepatic or adult myopathic forms carried at least one missense allele with residual enzyme activity. This genotype-severity correlation is significantly stronger in VLCADD than in the related MCAD deficiency, making variant classification clinically useful for anticipating prognosis. A large U.S. newborn screening cohort66 large U.S. newborn screening cohort
Miller et al. 2015, PMID 26385305, Mol Genet Metab 116:139–45 of 693 VLCAD-screen-positive infants found that approximately 57% carried only a single ACADVL pathogenic variant, emphasizing that heterozygous carrier detection is an inherent feature of population-based newborn screening for this condition.

Practical Implications

Single-copy carriers of p.Phe458Leu are metabolically normal and require no dietary modifications or monitoring. The clinical relevance is entirely reproductive: if both partners in a couple carry a pathogenic ACADVL variant — whether this variant or any other — each pregnancy has a 25% chance of producing a child with VLCAD deficiency. Because VLCADD is an autosomal recessive disorder with an estimated birth prevalence of 1 in 30,000–100,000, the chance that a random partner is also an ACADVL carrier is roughly 1 in 100–200. Carrier couple identification before pregnancy allows access to prenatal testing, preimplantation genetic testing (PGT), or informed expectant management.

VLCADD identified early — through newborn screening or family cascade testing — is highly treatable. Management centers on reducing dependence on very long-chain fat oxidation: a diet low in long-chain triglycerides (LCT) with MCT supplementation, strict avoidance of fasting, and L-carnitine supplementation in some cases. Triheptanoin (C7 fat), an odd-chain anaplerotic MCT, received FDA approval in 2020 for the management of long-chain fatty acid oxidation disorders including VLCADD. Outcomes for newborn-screen-identified infants treated from birth are substantially better than for those diagnosed after symptom onset.

Interactions

rs118204017 is one of many pathogenic ACADVL variants; rs11820401577 rs118204015 is a second ACADVL variant in this GeneOps batch. Compound heterozygosity for two ACADVL pathogenic variants — one on each chromosome — produces VLCAD deficiency in the same way as homozygosity; the severity depends on the residual enzyme activity of the two alleles combined. Compound heterozygosity for p.Phe458Leu and a null allele (the scenario in the original Cox 1998 case) produces a more severe phenotype than two missense alleles with partial residual activity. Carriers of rs118204017 who are also carriers of rs118204015 (or any other pathogenic ACADVL variant) on the opposite chromosome would be affected individuals, not unaffected carriers.

Genotype Interpretations

What each possible genotype means for this variant.

TT Non-carrier Normal

No ACADVL Phe458Leu variant — standard fatty acid oxidation enzyme function

You carry two copies of the common T allele at this position. Your VLCAD enzyme has the standard phenylalanine at residue 458, and your very long-chain fatty acid oxidation capacity is unaffected by this variant. The overwhelming majority of people share this genotype — the C allele appears in only about 1 in 40,000 chromosomes in population databases. No action is needed based on this result.

CT Carrier Carrier

One copy of ACADVL Phe458Leu — healthy carrier, relevant for reproductive planning

VLCAD deficiency is an autosomal recessive disorder: two disrupted ACADVL alleles are required to impair fatty acid oxidation. The p.Phe458Leu substitution disrupts the acyl-CoA substrate channel of the enzyme and has been found in affected individuals — most notably in the original 1998 case report by Cox et al. (PMID 9709714), where it occurred in trans with a splice site mutation in an infant with severe cardiomyopathy. Because it is in trans in that case, the isolated allele was not causing symptoms in a heterozygous parent.

The estimated birth prevalence of VLCADD is 1 in 30,000–100,000. At a carrier frequency of roughly 1 in 100–200 in the general population across all ACADVL pathogenic variants, the probability that a random reproductive partner also carries any ACADVL pathogenic variant is low. When both partners are identified as carriers before conception, each pregnancy has a 25% chance of VLCAD deficiency, 50% chance of carrier, and 25% chance of non-carrier status. Prenatal testing (CVS or amniocentesis) and preimplantation genetic testing (PGT-M) are available for carrier couples who wish to obtain information before or during pregnancy.

Newborn screening for VLCADD is now routine in most high-income countries, using acylcarnitine profiles from dried blood spots. Newborn-screen-identified infants treated from birth — primarily with a low long-chain fat, high-MCT diet and fasting avoidance — have dramatically better outcomes than those diagnosed after symptom onset. Cardiomyopathy that reverses with treatment, as seen in the Cox 1998 case, underscores the importance of early identification.

CC Homozygous Homozygous

Two copies of ACADVL Phe458Leu — consistent with VLCAD deficiency; metabolic evaluation needed

The p.Phe458Leu substitution reduces VLCAD enzyme activity to approximately 20% of normal when present as the sole mutation in functional studies, consistent with partial residual activity. Genotype-phenotype data from Andresen et al. 1999 (PMID 9973285) show that missense variants with residual activity are associated with milder phenotypes — the hepatic form with hypoketotic hypoglycemia or the adult myopathic form with exercise-induced rhabdomyolysis and muscle pain — rather than the severe neonatal cardiomyopathy associated with null alleles. However, the original Cox 1998 case with F458L was severe (compound heterozygous with a null splice site allele), so clinical severity in a homozygous p.Phe458Leu individual is not well-established and requires individual assessment.

The primary metabolic risk in VLCADD is the inability to sustain fat oxidation during prolonged fasting, illness, or high-intensity exercise. Very long-chain acylcarnitines (particularly C14:1-carnitine) accumulate and can be cardiotoxic and myotoxic. Dietary management centers on reducing dependence on very long-chain fatty acid oxidation: restriction of long-chain triglycerides (LCT), supplementation with medium-chain triglycerides (MCT) as an alternative energy substrate, avoidance of fasting, and emergency protocols during intercurrent illness. Triheptanoin (Dojolvi), an odd-chain anaplerotic C7 fat, is FDA-approved (2020) for long-chain fatty acid oxidation disorders.