rs121434280 — ACADM ACADM Y67H

ACADM Y67H — A Mild, Temperature-Sensitive Variant in the MCAD Enzyme

Every time you go more than a few hours without eating, your body shifts from burning dietary glucose to burning stored fat. This switch depends on fatty acid oxidation¹¹ fatty acid oxidation
the mitochondrial process of breaking down fatty acids into acetyl-CoA for energy production, generating ketone bodies as fuel for the brain and heart — and medium-chain fatty acids (C6–C12 carbon chains) are a major energy source during that transition. The enzyme that catalyzes their first oxidation step is MCAD²² MCAD
Medium-Chain Acyl-CoA Dehydrogenase, encoded by the ACADM gene on chromosome 1p31, a homotetramer assembled inside the mitochondrial matrix. Without functional MCAD, medium-chain fatty acids accumulate as acylcarnitines in blood and urine, ketones cannot be generated adequately, and blood glucose can drop to dangerous levels during fasting or illness.

The c.199T>C variant (rs121434280) causes a tyrosine-to-histidine substitution at position 67 of the MCAD protein (p.Tyr67His, also historically noted as Y42H using mature-protein numbering). This variant is listed as Pathogenic in ClinVar³³ ClinVar
VCV000003597, 2-star classification from 16 independent laboratory submissions and is referenced in OMIM⁴⁴ OMIM
Entry 607008.0011 as one of the catalogued ACADM allelic variants. Its clinical meaning, however, is substantially milder and more context-dependent than classic MCAD-deficiency mutations — making it one of the most instructive examples of how the same "pathogenic" label can span a wide spectrum of biological effect.

The Mechanism

Tyr67 sits in the N-terminal α-helical domain of MCAD and contributes to the correct folding and tetramer assembly of the enzyme. The Y67H substitution introduces a histidine residue whose altered side-chain geometry subtly destabilizes the local protein fold. At normal body temperature (37°C), the mutant protein retains substantial catalytic activity — measured in multiple independent studies at 45–91% of wild-type⁵⁵ 45–91% of wild-type
Jank JM et al. The domain-specific and temperature-dependent protein misfolding phenotype of variant medium-chain acyl-CoA dehydrogenase. PLoS One, 2014.

The critical feature of Y67H is its temperature dependence: higher temperature shifts the protein toward misfolded, aggregated conformations, progressively reducing its activity. This means that during a febrile illness — when core body temperature may reach 39–40°C — the residual MCAD activity in a Y67H carrier can drop significantly. In an individual who is compound heterozygous (carrying Y67H on one chromosome and a more disruptive mutation on the other), this fever-induced loss of the Y67H allele's residual contribution can tip the balance toward clinically meaningful MCAD insufficiency.

A landmark study on enzyme activity thresholds established⁶⁶ established
Tucci S et al. Genotype and residual enzyme activity in MCAD deficiency: Are predictions possible? J Inherit Metab Dis, 2021 that residual MCAD activity above ~30% is sufficient to prevent clinical disease. Y67H homozygotes, with activities in the 45–91% range, fall well above this threshold under normal physiological conditions. Compound heterozygotes, however, may approach the critical range during fever.

The Evidence

Newborn screening has been essential in characterizing this variant's population frequency and clinical profile. In a landmark Bavarian screening study of 524,287 neonates, Maier et al.⁷⁷ Maier et al.
Maier EM et al. Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening. Hum Mutat, 2005 identified c.199T>C (Y67H) in 9 of 57 MCADD-positive newborns, with 6 of these 9 being compound heterozygous with the severe c.985A>G (K329E) allele. None of the Y67H homozygotes developed clinical MCADD.

A separate functional analysis by Sturm et al.⁸⁸ Sturm et al.
Sturm M et al. Functional effects of different MCAD genotypes and identification of asymptomatic variants. PLoS One, 2012 measured octanoyl-CoA oxidation rates in lymphocytes from 65 newborns and found that individuals carrying c.199T>C showed residual activities of 31–60%, "clearly in the range of proven heterozygotes that do not have a risk of symptomatic disease." Based on this, the authors classified c.199T>C as likely biochemically mild when homozygous.

The population carrier frequency for Y67H is approximately 1 in 500⁹⁹ population carrier frequency for Y67H is approximately 1 in 500
O'Reilly L et al. The Y42H mutation in medium-chain acyl-CoA dehydrogenase, which is prevalent in babies identified by MS/MS-based newborn screening, is temperature sensitive. Eur J Biochem, 2004, making it one of the three most prevalent pathogenic ACADM alleles in people of European ancestry. Its global gnomAD allele frequency is ~0.05% (roughly 140/282,000 alleles).

Practical Actions

For individuals homozygous for Y67H, current evidence suggests that clinical MCAD deficiency is unlikely. However, because body temperature during illness can meaningfully reduce Y67H MCAD activity, it is prudent for homozygotes to know that febrile illnesses are a trigger for caution — early antipyretic treatment and maintaining caloric intake during fever episodes are advisable.

For heterozygous carriers, the single C allele produces no clinical risk — one functional ACADM copy is sufficient. The primary concern for carriers is reproductive: if both parents carry pathogenic ACADM variants (whether Y67H or other mutations), each pregnancy has a 25% probability of compound heterozygosity. Because compound heterozygotes pairing Y67H with a more severe allele (especially K329E, rs77931234) may have clinically significant MCAD deficiency requiring dietary and emergency management, carrier couples should discuss this with a genetic counselor before or during pregnancy.

Interactions

The most clinically important interaction for this variant is compound heterozygosity with rs77931234 (ACADM K329E). K329E is the most common severe MCAD allele (~67% of defective alleles in European newborns), with residual activity near zero when homozygous. Individuals who carry Y67H on one chromosome and K329E on the other have a combined MCAD activity that depends partly on the Y67H allele's temperature-sensitive contribution. At normal temperature they may have borderline-sufficient activity, but during fever the combined deficiency can become symptomatic — requiring fasting avoidance, high-glucose oral intake, and IV dextrose if unable to tolerate oral feeding. This gene-gene (allele-allele) interaction is well-documented in newborn screening literature and should be flagged to families where both alleles are identified.