rs200788251 — ACADVL ACADVL p.Gly289Arg

Pathogenic missense variant in ACADVL encoding VLCAD; heterozygous carriers are asymptomatic, while biallelic carriers develop VLCAD deficiency—a fatty acid oxidation disorder with phenotypes ranging from neonatal cardiomyopathy to exercise-induced rhabdomyolysis

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ACADVL p.Gly289Arg — A Pathogenic Variant in the Long-Chain Fat Burning Engine

Every time your body burns fat for energy during fasting, sleep, or prolonged exercise, it relies on a chain of enzymes inside the mitochondria. The first and rate-limiting step for very long-chain fatty acids (14–20 carbons) is carried out by very-long-chain acyl-CoA dehydrogenase11 very-long-chain acyl-CoA dehydrogenase
VLCAD — encoded by ACADVL on chromosome 17p13. The enzyme sits on the inner mitochondrial membrane and initiates beta-oxidation of long-chain fatty acids, producing the acetyl-CoA and reduced electron carriers (FADH₂) that feed the Krebs cycle and electron transport chain. This SNP, rs200788251, represents a c.865G>A transition that replaces the glycine at position 289 with the much bulkier, positively charged arginine (p.Gly289Arg). Glycine-289 sits in a structurally conserved region of the enzyme and is under strong evolutionary constraint; the substitution reduces VLCAD activity to approximately 15% of normal in vitro.

The Mechanism

VLCAD22 VLCAD
very-long-chain acyl-CoA dehydrogenase, a homodimeric flavoprotein that removes two hydrogen atoms from the acyl-CoA thioester, generating a trans-2-enoyl-CoA and transferring electrons to electron transfer flavoprotein (ETF) for entry into the respiratory chain depends on precise folding of its active site for catalysis. The p.Gly289Arg substitution introduces a bulky, charged side chain where glycine's compact structure is required for proper protein folding. Functional studies demonstrate that fibroblasts from a compound heterozygous individual carrying the p.Gly289Arg allele alongside a second pathogenic variant showed no detectable enzyme activity and absent protein expression on western blot — indicating the substitution causes protein misfolding and accelerated degradation.

Because ACADVL operates as a homodimer, a single non-functional allele (the heterozygous carrier state) still produces enough functional enzyme dimers — with approximately 50% enzyme activity — to support normal fatty acid oxidation under ordinary dietary conditions. Disease emerges only when both alleles are compromised.

The Evidence

The variant is classified likely pathogenic by the ClinGen ACADVL Variant Curation Expert Panel33 likely pathogenic by the ClinGen ACADVL Variant Curation Expert Panel
ClinVar VCV000370981, 4-star expert panel review, last evaluated June 2023, based on ACMG/AMP classification criteria. All twelve diagnostic laboratory submitters in ClinVar classify the variant as pathogenic or likely pathogenic. The glycine at codon 289 is conserved across vertebrates, computational tools (SIFT, PolyPhen-2) predict a deleterious effect, and in vitro functional studies confirm the consequence.

A US newborn screening study of 693 individuals44 US newborn screening study of 693 individuals
Pena et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab, 2016 identified p.Gly289Arg on six alleles from affected individuals, establishing it among the recurrent pathogenic alleles seen in clinical practice in the United States.

VLCAD deficiency occurs in approximately 1 in 30,000–100,000 births. Expanded newborn screening with acylcarnitine profiling — measuring C14:1 acylcarnitine55 C14:1 acylcarnitine
tetradecadienoylcarnitine, the characteristic accumulation product of impaired VLCAD-mediated beta-oxidation; a C14:1 level above 1 µmol/L on dried blood spot strongly suggests VLCAD deficiency — now identifies most affected individuals presymptomatically.

Three phenotypes are documented in homozygous or compound heterozygous individuals: - Severe neonatal form: cardiomyopathy (hypertrophic or dilated), pericardial effusion, arrhythmia, and metabolic crisis in the first weeks of life — historically associated with significant mortality. - Infantile hepatic form: hypoketotic hypoglycemia, hepatomegaly, and liver dysfunction, typically presenting during intercurrent illness. - Late-onset myopathic form: the most common presentation in the current NBS era — episodic rhabdomyolysis triggered by prolonged exercise, fasting, or illness; muscle cramps, pain, dark urine (myoglobinuria), and markedly elevated creatine kinase (CK).

Practical Actions

Heterozygous carriers (AG genotype) are clinically asymptomatic. The primary practical significance of carrier status is reproductive: if both parents carry ACADVL pathogenic variants, each child has a 25% risk of VLCAD deficiency. Partner carrier testing before or during pregnancy is the key action.

For individuals with biallelic pathogenic variants (AA genotype, or compound heterozygous for two different ACADVL pathogenic alleles), the consensus-based nutrition management guidelines66 consensus-based nutrition management guidelines
Vockley et al. 2021, Mol Genet Metab. PMID 33093005 recommend: avoidance of fasting (using age-appropriate maximum fasting intervals), restriction of long-chain fatty acid intake, MCT supplementation as an alternative fat source bypassing the enzymatic block, and carnitine supplementation to support acylcarnitine clearance. During exercise, consuming easily metabolized carbohydrates before and after activity significantly reduces rhabdomyolysis risk.

Interactions

This variant causes disease in the autosomal recessive setting: a second loss-of-function ACADVL variant on the other chromosome must be present. Most affected patients identified through newborn screening are compound heterozygous (two different pathogenic variants) rather than homozygous for p.Gly289Arg. Genotyping at this single SNP position will detect the AG carrier state but cannot determine whether a second pathogenic variant exists elsewhere in ACADVL — full gene sequencing is required for a complete clinical picture in symptomatic individuals or those with positive NBS results.

Nutrient Interactions

long-chain fatty acids altered_metabolism
carnitine increased_need

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-carrier Normal

No ACADVL p.Gly289Arg variant detected

You carry two copies of the common G allele at rs200788251 and do not carry the p.Gly289Arg pathogenic variant. Your VLCAD enzyme at this position is structurally intact.

This is the genotype for approximately 99.97% of the general population. VLCAD deficiency arising from this specific variant does not apply to you.

AG Carrier Carrier

Carrier of one ACADVL p.Gly289Arg pathogenic allele

Clinical literature uniformly documents that obligate heterozygous carriers of ACADVL pathogenic variants — parents of affected children — are asymptomatic. Biochemical testing (acylcarnitine profiling) is unreliable for distinguishing carriers from non-carriers; molecular genetic testing of known family variants is the preferred approach.

The key action for AG carriers is partner carrier testing before or during pregnancy. Expanded carrier screening panels offered commercially include ACADVL sequencing. If both partners carry ACADVL pathogenic variants, each pregnancy has a 25% chance of biallelic disease, a 50% chance of producing another carrier, and a 25% chance of no pathogenic allele. Prenatal or preimplantation diagnosis is available when both parental mutations are known.

Note that a single SNP test at rs200788251 can confirm carrier status for this specific variant but does not survey the rest of the ACADVL gene. If family history suggests VLCAD deficiency or a partner's carrier test is positive for a different ACADVL variant, full gene sequencing is appropriate.

AA Homozygous — VLCAD Deficiency Homozygous

Two copies of the ACADVL p.Gly289Arg pathogenic allele — VLCAD deficiency

VLCAD deficiency (OMIM #201475) presents across three clinical phenotypes, with severity correlating broadly with residual enzyme activity:

  1. Severe neonatal cardiac form: cardiomyopathy (hypertrophic or dilated), pericardial effusion, and arrhythmia in the first weeks of life. Without treatment, historically associated with significant early mortality.
  2. Infantile hepatic form: hypoketotic hypoglycemia, hepatomegaly, and liver dysfunction — classically triggered by fasting or intercurrent illness. The hypoketotic state reflects failure to generate ketone bodies from long-chain fat during fasting; the brain, which relies on ketones as a fasting fuel, is deprived at the moment it most needs them.
  3. Late-onset myopathic form: the predominant presentation in individuals identified through newborn screening — episodic rhabdomyolysis (muscle breakdown) triggered by prolonged exercise, fasting, or febrile illness. Symptoms include muscle pain, weakness, and dark (tea-colored) urine from myoglobinuria. Serum creatine kinase can reach tens of thousands of U/L during episodes.

The cornerstone of treatment is metabolic management: avoiding fasting beyond age-appropriate limits, restricting long-chain fat intake, and providing medium-chain triglycerides (MCT) as an alternative fat source that bypasses the VLCAD enzymatic block. The FDA-approved drug triheptanoin — an anaplerotic odd-chain triglyceride — is available for individuals with confirmed long-chain fatty acid oxidation disorders and may reduce rhabdomyolysis episodes compared to MCT oil alone.

Acylcarnitine profiling (C14:1, C14:2, C14, C12:1) is the key monitoring biomarker. Elevated C14:1 acylcarnitine reflects the backup of VLCAD substrates and is used both for diagnosis and treatment monitoring.