rs118204015 — ACADVL

ACADVL K382Q — A Pathogenic Fatty Acid Oxidation Variant and Its Carrier Implications

Inside every mitochondrion, a molecular relay strips energy from fat molecules two carbons at a time in a process called beta-oxidation¹¹ beta-oxidation
Beta-oxidation is the main pathway by which cells convert dietary and stored fat into ATP, particularly during fasting, prolonged exercise, and periods of high energy demand. Very long-chain acyl-CoA dehydrogenase (VLCAD), encoded by the ACADVL gene on chromosome 17, catalyzes the critical first step in this relay for fatty acids with chain lengths of 14–20 carbons — the very long-chain fats found abundantly in foods like meat, dairy, and vegetable oils. When VLCAD fails, these long-chain fats accumulate as toxic acylcarnitines and cannot be converted to energy, causing VLCAD deficiency (OMIM #201475)²² VLCAD deficiency (OMIM #201475)
An autosomal recessive inborn error of metabolism affecting 1 in 30,000–100,000 births; listed on all US newborn screening panels since the early 2000s in its most severe forms.

The c.1144A>C variant (K382Q, p.Lys382Gln) substitutes a positively charged lysine for a neutral glutamine at position 382, within a region critical for FAD cofactor binding. This single change is sufficient to abolish VLCAD function. The variant was first identified by Souri et al. in ³³ Souri M et al., Am J Hum Genet, 1996 in a patient with VLCAD deficiency and confirmed pathogenic through expression experiments: CHO cells transfected with K382Q cDNA showed no detectable VLCAD enzyme activity and produced a protein with abnormal dimer assembly — structurally broken rather than merely impaired.

The Mechanism

VLCAD functions as a homodimer anchored to the inner mitochondrial membrane. Lysine-382 sits within the FAD-binding domain; its positive charge is required for proper folding of the subunit interface. The K382Q substitution eliminates this charge, disrupting dimer assembly. The resulting misfolded protein is rapidly degraded — VLCAD activity drops to effectively zero in homozygous or compound heterozygous affected individuals ⁴⁴ ClinGen ACADVL Expert Panel review (Dec 2022): functional data shows 19% residual activity via enzymatic assay; REVEL pathogenicity score 0.95. Carriers with one functional copy produce enough VLCAD to oxidize long-chain fats normally — heterozygotes are asymptomatic and have normal VLCAD activity in lymphocyte and fibroblast assays.

The Evidence

ClinVar classifies K382Q as likely pathogenic (Variation ID 1628), reviewed by the ClinGen ACADVL Variant Curation Expert Panel (4-star expert review, December 2022), with supporting submissions from Labcorp Genetics, Baylor Genetics, and Myriad Genetics. The OMIM allelic variant entry (609575.0008) documents the original 1996 pathogenic characterization.

In a study of Japanese VLCAD patients, K382Q accounted for 12.7% of mutant alleles in the pre-newborn-screening cohort⁵⁵ K382Q accounted for 12.7% of mutant alleles in the pre-newborn-screening cohort
Osawa et al., Mol Genet Metab, 2022 — frequency fell to 3.1% in the expanded NBS cohort, reflecting ascertainment bias toward milder variants in a screened population, establishing it as one of the more clinically significant ACADVL variants.

Functional fibroblast studies⁶⁶ Functional fibroblast studies
Schiff et al., Mol Genet Metab, 2013 demonstrate that heterozygous carriers show normal VLCAD enzyme activity — confirming that a single functional copy is sufficient for normal fatty acid oxidation. This is the biochemical basis for why VLCAD deficiency follows autosomal recessive inheritance and why carrier individuals require no clinical management for themselves.

The variant is extremely rare in gnomAD v4 (1 in ~149,000 alleles, global), consistent with strong negative selection against loss-of-function VLCAD variants.

Practical Actions

Carriers of K382Q (AC genotype) are healthy and require no dietary restrictions or treatment for themselves. The clinical relevance is reproductive: if both partners carry a pathogenic ACADVL variant (from any combination of the 200+ known pathogenic/likely-pathogenic alleles), each pregnancy has a 25% chance of being affected. VLCAD-affected infants are identified by newborn screening via elevated C14:1 acylcarnitine; early dietary management (MCT-enriched, long-chain fat-restricted diet) prevents the most severe outcomes including cardiomyopathy and hypoglycemic crises.

Carriers may wish to confirm their partner's ACADVL carrier status through comprehensive gene sequencing — a panel approach is more informative than single-variant testing given the allelic heterogeneity of this gene.

Interactions

VLCAD deficiency (the disease) is a compound heterozygous or homozygous condition in most patients. K382Q has been documented in affected individuals in compound heterozygosity with other ACADVL variants such as the common p.V283A (c.848T>C) variant and various splice-site and truncating mutations. The severity of the resulting deficiency depends on the residual activity of the second allele: null+null combinations cause severe neonatal cardiac disease, while hypomorphic+null combinations (like many c.848T>C compound heterozygotes) cause milder myopathic presentations. K382Q is a functional null, so its severity in an affected child is determined primarily by the partner allele.