rs121434281 — ACADM S245L

ACADM S245L — A Rare Cause of MCAD Deficiency

Every cell in your body can burn glucose for energy, but most tissues — especially the heart, skeletal muscle, and liver — rely heavily on fatty acids as a fuel source during fasting, exercise, and illness. Medium-chain fatty acids (carbon chain lengths C6–C12) are processed by a dedicated mitochondrial enzyme called medium-chain acyl-CoA dehydrogenase (MCAD), encoded by the ACADM gene. When MCAD is impaired, the body cannot mobilize stored fat efficiently during metabolic stress, and the resulting fuel shortage can cause hypoketotic hypoglycemia¹¹ hypoketotic hypoglycemia
Low blood glucose without the compensating rise in ketone bodies (the brain's alternative fuel) that normally occurs during fasting. This combination is more dangerous than simple hypoglycemia because the brain is deprived of both its primary and emergency fuel. — which, untreated, can progress to seizures, coma, or death.

The c.734C>T variant (rs121434281) substitutes a leucine for the serine at position 245 of the mature MCAD protein (p.Ser245Leu). This rare missense change was first described in 2001 and is classified as Pathogenic/Likely pathogenic in ClinVar (VCV000003598) based on 13 independent submissions from diagnostic laboratories including Invitae, GeneDx, and LabCorp.

The Mechanism

MCAD is a homotetrameric²² homotetrameric
Four identical subunits assembled into a single functional enzyme complex inside the mitochondria enzyme that sits at the first step of the beta-oxidation spiral for medium-chain fatty acids. It extracts electrons from fatty acyl-CoA substrates and transfers them to the electron transfer flavoprotein (ETF)³³ electron transfer flavoprotein (ETF)
A mitochondrial protein that shuttles electrons from several dehydrogenases (including MCAD) to the main respiratory chain. ETFA and ETFB gene variants cause a separate condition, multiple acyl-CoA dehydrogenase deficiency (MADD)., coupling fatty acid breakdown to ATP production.

Serine-245 sits within the substrate-binding region of the MCAD protein. The Ser→Leu substitution introduces a bulkier, hydrophobic side chain into a position normally occupied by a polar residue, disrupting local folding and reducing enzyme activity. Functional studies in patients⁴⁴ Functional studies in patients
Zschocke J et al. Molecular and functional characterisation of mild MCAD deficiency. Hum Genet, 2001 carrying this variant homozygously showed residual MCAD activities falling between classical MCAD deficiency (near-zero activity) and obligate heterozygotes — indicating partial, not complete, loss of function.

Because MCAD deficiency is autosomal recessive, a single copy of S245L (heterozygous carrier) does not impair fatty acid oxidation: one functional ACADM allele is sufficient for normal MCAD activity. Disease occurs only when a person inherits two pathogenic ACADM alleles — either S245L homozygous or compound heterozygous with another pathogenic variant such as the common K304E (c.985A>G) founder mutation.

The Evidence

MCAD deficiency is the most common inherited disorder of fatty acid oxidation, with overall incidence of approximately 1 in 10,000–17,000 live births in populations of northern European descent. The K304E (K329E) variant⁵⁵ The K304E (K329E) variant
Historically called K329E due to inclusion of the 20-amino-acid mitochondrial targeting sequence in older protein numbering; the mature protein numbering gives K304E. Both terms refer to the same variant. accounts for roughly 80–90% of all MCAD deficiency alleles in northern Europeans due to a founder effect⁶⁶ founder effect
A dramatic reduction in allele diversity caused by the descent of a large population from a small ancestral group, as occurred in northern European populations in which the K304E mutation became prevalent.

The S245L variant is far rarer — the T allele frequency is approximately 0.000015 in gnomAD (21 alleles in 1.4 million sequenced), consistent with an ultra-rare pathogenic allele. No homozygotes are recorded in gnomAD.

The first clinical report⁷⁷ The first clinical report
Zschocke J et al. Molecular and functional characterisation of mild MCAD deficiency. Hum Genet, 2001 identified S245L in an infant with a mildly abnormal newborn screening acylcarnitine profile who was homozygous for the mutation due to consanguinity. Urinary organic acids were completely normal, and phenylpropionic acid loading tests were normal — features consistent with a mild (not classical) MCAD deficiency phenotype with meaningful residual enzyme activity. This contrasts with classical MCAD deficiency (typically biallelic K304E), which produces striking organic aciduria and no residual activity.

Practical Actions

For heterozygous carriers, no dietary or supplemental intervention is required. The principal relevance is reproductive: if a carrier's partner also carries a pathogenic ACADM variant, each pregnancy has a 25% chance of producing an affected child.

For affected individuals (homozygous S245L or compound heterozygous with another ACADM pathogenic variant), management per GeneReviews⁸⁸ GeneReviews
Chang IJ, Lam C, Vockley J. Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. GeneReviews, 2024 centres on three principles: (1) strict avoidance of prolonged fasting at all ages; (2) emergency glucose supplementation during illness or surgery; and (3) avoidance of medium-chain triglyceride (MCT)-containing products, ketogenic diets, and binge alcohol consumption, all of which can trigger metabolic decompensation.

Well-managed patients with MCAD deficiency can lead entirely normal lives. The condition is routinely detected through newborn screening in most high-income countries; early identification prevents the first — often life-threatening — metabolic crisis.

Interactions

Compound heterozygosity is the most clinically important interaction for this SNP. An individual who carries S245L on one ACADM allele and the common K304E variant (c.985A>G, rs77931234) on the other will have biallelic ACADM deficiency and a clinical phenotype similar to classical MCAD deficiency. The Zschocke 2001 paper documented exactly this combination in two other patients in the same cohort (K304E + Y67H), showing that compound heterozygous individuals can have more severe biochemical findings than S245L homozygotes. Supervisors should consider a compound action for rs121434281 CT + rs77931234 AG (or other confirmed pathogenic ACADM variants) once those entries are in the catalog.