rs121434280 — ACADM ACADM Y67H

Pathogenic missense variant in the MCAD enzyme causing a temperature-sensitive reduction in fatty acid oxidation capacity; homozygous individuals retain substantial residual activity and are likely asymptomatic, but compound heterozygotes pairing this allele with a more severe ACADM variant are at risk for MCAD deficiency

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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.

Nutrient Interactions

medium-chain fatty acids impaired_conversion

Genotype Interpretations

What each possible genotype means for this variant.

TT Non-Carrier Normal

Normal MCAD function — full fatty acid oxidation capacity

With two copies of the reference allele, you produce fully functional MCAD enzyme with normal thermal stability and catalytic activity. Your mitochondria can oxidize medium-chain fatty acids (C6–C12) without impairment during fasting or caloric restriction. No special dietary precautions are needed based on this variant.

CT Carrier Carrier

Heterozygous carrier — one Y67H allele, full MCAD function under normal conditions

Single-allele carriers of Y67H have one MCAD copy that folds normally and one that folds with reduced efficiency at physiological temperature. The net result is approximately 50–75% of wild-type MCAD activity in heterozygotes, which is well above the ~30% threshold below which clinical MCADD occurs. Carriers do not develop MCAD deficiency symptoms.

The primary significance of carrier status is reproductive. If your partner also carries any pathogenic ACADM variant (Y67H or another pathogenic allele such as K329E), each pregnancy faces a 25% probability of compound heterozygosity, which can result in clinically significant MCAD deficiency requiring dietary management from birth. Y67H + K329E compound heterozygosity is the most commonly encountered combination and is associated with intermediate-to-mild MCAD deficiency phenotype, with illness-triggered metabolic risk.

CC Homozygous Y67H Homozygous

Homozygous Y67H — temperature-sensitive MCAD with substantial residual activity; likely asymptomatic but monitor during fever

The Y67H variant produces a temperature-sensitive MCAD protein. At 37°C, enzyme activity is substantially preserved (45–91% WT), placing homozygotes well above the ~30% residual-activity threshold below which MCADD is clinically confirmed. Research by Jank et al. (PLoS One, 2014) showed that elevated temperature pushes Y67H protein toward misfolded conformations, lowering activity — meaning febrile illness is the primary risk window.

Functional classification by Sturm et al. (PLoS One, 2012) specifically categorized c.199T>C homozygous individuals in the range of "proven heterozygotes that do not have a risk of symptomatic disease," indicating that homozygous Y67H is likely a biochemically mild or asymptomatic genotype in most circumstances.

Newborn screening will typically detect an abnormal C8 acylcarnitine in homozygous Y67H newborns, leading to confirmatory testing. Many such infants are identified and then found to have intermediate or borderline biochemical profiles. Close metabolic follow-up in the first years of life and clear emergency fever protocols are appropriate given the temperature-sensitive nature of the variant.