rs387906249 — ACADVL c.343del (p.Glu115Lysfs*2)

Pathogenic ACADVL frameshift deletion causing premature protein truncation; heterozygous carriers are healthy but carry reproductive risk, while biallelic disruption causes VLCAD deficiency requiring lifelong dietary management

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ACADVL c.343del — A Null Allele in the Fatty Acid Engine

Every cell in the body can burn fat for fuel, but only if the right enzymes are present to start the process. Very long-chain acyl-CoA dehydrogenase (VLCAD)11 Very long-chain acyl-CoA dehydrogenase (VLCAD)
Encoded by ACADVL on chromosome 17p13.1; a homodimeric flavoenzyme anchored to the inner mitochondrial membrane that catalyzes the first step of beta-oxidation for fatty acids with 14–20 carbon chains is the gatekeeper for very long-chain fats — the dominant form of stored body fat and a critical fuel during fasting, fever, prolonged exercise, and the newborn period. The rs387906249 variant is a single guanine deletion at coding position 343 (NM_000018.4:c.343del), which shifts the reading frame after exon 6 and introduces a premature stop codon just two codons into the new frame (p.Glu115Lysfs*2). The result is a severely truncated protein that undergoes nonsense-mediated mRNA decay — one functional ACADVL copy is silenced entirely.

This deletion was first described by Strauss et al. in 199522 first described by Strauss et al. in 1995
PNAS 1995; the authors identified a single-base deletion at the intron-exon 6 boundary of ACADVL in a child who died suddenly with hypertrophic cardiomyopathy, compound heterozygous with a second missense mutation (p.Arg613Trp) in a child who died with hypertrophic cardiomyopathy — one of the original VLCAD deficiency cases that established fatty acid oxidation disorders as a cause of sudden cardiac death in infancy. The variant has since been documented in multiple affected individuals across diverse ethnic backgrounds and has been classified Pathogenic33 Pathogenic
ClinVar VCV000001624; reviewed by the ClinGen ACADVL Variant Curation Expert Panel in November 2021 — 3-star review status; ACMG criteria: PVS1, PM2_Supporting, PP4 by the ClinGen ACADVL Variant Curation Expert Panel.

The Mechanism

VLCAD is anchored to the inner mitochondrial membrane and functions as a homodimer. Each cycle of very long-chain fatty acid beta-oxidation begins when VLCAD strips two hydrogen atoms from the acyl-CoA thioester, transferring them to FAD and passing the electrons into the electron transport chain. Without functional VLCAD, very long-chain acylcarnitines (particularly C14:1-carnitine44 C14:1-carnitine
Tetradecenoylcarnitine; elevated C14:1 on a dried blood spot is the primary newborn screening marker for VLCAD deficiency, and the level correlates inversely with residual enzyme activity) accumulate to toxic levels in heart muscle, skeletal muscle, and liver.

The c.343del frameshift predicts complete loss of VLCAD protein from the affected allele — the truncated mRNA is degraded by the cell's own quality-control machinery before it can be translated. Carriers with one intact allele produce sufficient VLCAD for normal fatty acid oxidation. Individuals with two loss-of-function ACADVL alleles (whether homozygous for this deletion or compound heterozygous with a second pathogenic variant) have no residual VLCAD activity and develop VLCAD deficiency.

The Evidence

The genotype-phenotype correlation in VLCAD deficiency55 genotype-phenotype correlation in VLCAD deficiency
Andresen et al. 1999, Am J Hum Genet 64:479–494 is among the clearest in inborn errors of metabolism: patients with two null alleles (frameshift, nonsense, or splice-site mutations that abolish protein production) develop the most severe form — hypertrophic or dilated cardiomyopathy presenting in the first months of life, with risk of sudden death if unrecognized. Patients with at least one missense allele that preserves partial enzyme activity develop milder presentations: episodic hypoglycemia and hepatomegaly in childhood, or exercise-induced rhabdomyolysis in adults. The c.343del deletion, as a complete null allele, places compound heterozygous individuals at risk for severe disease when paired with another null allele, and at intermediate risk when paired with a hypomorphic missense allele.

In 52 VLCAD patients identified through newborn screening66 52 VLCAD patients identified through newborn screening
Merritt et al. 2016, Mol Genet Metab 117:225–231, null alleles in compound heterozygous combinations predisposed to cardiomyopathy, while the most common mild variant p.Val283Ala (c.848T>C) in combination with any allele produced uniformly non-cardiac presentations. VLCAD-affected infants identified and treated from birth through newborn screening have dramatically better outcomes than those diagnosed after a metabolic crisis. The key intervention is reducing dependence on very long-chain fat oxidation: a diet low in long-chain triglycerides (LCT), enriched with medium-chain triglycerides (MCT), with strict fasting avoidance. Triheptanoin (Dojolvi)77 Triheptanoin (Dojolvi)
An odd-chain synthetic C7 triglyceride that provides anaplerotic substrates to the Krebs cycle; FDA-approved for long-chain fatty acid oxidation disorders in June 2020 was approved by the FDA in 2020 as a more targeted alternative to standard MCT oil.

Practical Actions

Heterozygous carriers of c.343del are clinically healthy and require no dietary change or metabolic monitoring for themselves. The significance is reproductive: if both partners carry pathogenic ACADVL variants, each pregnancy has a 25% risk of VLCAD deficiency. Because VLCAD deficiency is autosomal recessive and over 200 pathogenic ACADVL alleles are known, comprehensive gene sequencing (not single-variant testing) is the most informative approach for partner carrier testing.

For individuals with biallelic pathogenic ACADVL variants — whether detected by newborn screening or later in life — management centers on four pillars: (1) long-chain fat restriction with MCT enrichment, (2) strict avoidance of fasting beyond age-appropriate safe intervals (4–6 hours for adults; shorter for infants and young children), (3) carbohydrate supplementation before and during prolonged exercise, and (4) a written emergency protocol for intercurrent illness specifying IV dextrose. Acylcarnitine monitoring (C14:1 on dried blood spot or plasma) guides dietary management intensity and early detection of metabolic stress.

Interactions

As a null ACADVL allele, c.343del causes VLCAD deficiency in compound heterozygous combinations with any other pathogenic ACADVL variant. The severity of the resulting phenotype depends primarily on the partner allele's residual enzyme activity. Compound heterozygosity with another null allele (such as a splice-site or nonsense mutation) typically produces the severe neonatal cardiomyopathy form. Compound heterozygosity with the hypomorphic p.Val283Ala (c.848T>C) allele — the most common VLCAD-associated variant in the US — produces the milder myopathic or hepatic form. rs200788251, another commonly reported ACADVL pathogenic variant, can cause VLCAD deficiency in compound heterozygosity with rs387906249. Carriers who also carry any second ACADVL pathogenic variant on the opposite chromosome are affected individuals, not carriers.

Nutrient Interactions

long-chain fatty acids altered_metabolism
medium-chain triglycerides increased_need

Genotype Interpretations

What each possible genotype means for this variant.

II Non-carrier Normal

No ACADVL c.343del deletion detected — normal VLCAD gene copy at this position

You carry two intact copies of the ACADVL gene at this position. The c.343del deletion is not present on either chromosome. Your VLCAD enzyme production is unaffected by this variant. The deletion allele is exceptionally rare — it appears in approximately 3 in 100,000 chromosomes globally in gnomAD — so this is the result found in essentially the entire general population.

DI Carrier Carrier

Carrier of one ACADVL c.343del deletion — healthy carrier with reproductive significance

The c.343del deletion is a complete null allele — the deleted reading frame causes premature protein truncation (p.Glu115Lysfs*2) and the resulting mRNA is degraded by nonsense-mediated decay before it can be translated. However, one intact ACADVL copy is fully sufficient for normal VLCAD enzyme activity. Functional studies confirm that fibroblasts from heterozygous carriers show normal VLCAD activity, consistent with the autosomal recessive inheritance pattern.

VLCAD deficiency affects an estimated 1 in 30,000–100,000 individuals and presents across a clinical spectrum: severe neonatal cardiomyopathy (associated with two null alleles), childhood episodic hypoglycemia and hepatomegaly, or adult-onset exercise-induced rhabdomyolysis. Because over 200 pathogenic ACADVL variants are known, partner screening should use full gene sequencing rather than single-variant testing to capture the full allelic spectrum. VLCAD deficiency identified through newborn screening (via elevated C14:1 acylcarnitine on dried blood spot) and treated early with a long-chain fat-restricted, MCT-enriched diet has dramatically better outcomes than disease diagnosed after a metabolic crisis.

DD Homozygous (Affected) Homozygous

Two copies of ACADVL c.343del — consistent with VLCAD deficiency requiring specialist evaluation

The c.343del deletion is a null allele — it abolishes VLCAD protein production through nonsense-mediated mRNA decay. Two null alleles eliminate VLCAD enzyme activity entirely, which is the molecular basis for the most severe VLCAD deficiency phenotype. The landmark genotype-phenotype study by Andresen et al. 1999 (PMID 9973285) demonstrated that patients with two null alleles (frameshift, splice-site, or nonsense mutations) consistently present with the severe early-onset form: hypertrophic or dilated cardiomyopathy in the first months of life, with risk of sudden death if undiagnosed.

The primary metabolic problem is the inability to oxidize very long-chain fatty acids (C14–C20) during energy-demanding states. When glycogen stores are depleted by fasting, fever, or prolonged exercise, the body normally switches to fat oxidation — this switch fails in VLCAD deficiency. Very long-chain acylcarnitines, particularly C14:1-carnitine, accumulate and are directly toxic to cardiac and skeletal muscle. The hallmark biomarker on newborn screening or plasma acylcarnitine profiling is elevated C14:1.

Treatment is highly effective when instituted early: restricting dietary long-chain triglycerides (LCT) to 10–15% of total calories, replacing them with medium-chain triglycerides (MCT) that bypass the VLCAD block, and strictly avoiding fasting prevents the accumulation of toxic acylcarnitines. The FDA approved triheptanoin (Dojolvi, 2020) as a structured anaplerotic C7 MCT for long-chain fatty acid oxidation disorders. Emergency IV dextrose protocols during intercurrent illness (vomiting, fever, inability to eat) are essential to prevent acute metabolic decompensation.