rs3832024 — FMO3 FMO3 c.591_592del

A 2-bp frameshift deletion in FMO3 that creates a premature stop codon at position 197, completely abolishing the enzyme's ability to convert trimethylamine (TMA) to odorless TMAO — the primary genetic cause of trimethylaminuria (fish odor syndrome) in East Asian populations.

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FMO3 c.591_592del — The Frameshift That Causes Fish Odor Syndrome

The smell of fish is produced by trimethylamine11 trimethylamine
TMA: a volatile, pungent amine produced when gut bacteria ferment choline, lecithin, and other dietary compounds containing trimethylamine precursors. In most people, TMA is rapidly oxidized to odorless trimethylamine N-oxide (TMAO) in the liver by the enzyme FMO3 — flavin-containing monooxygenase 3. When FMO3 fails, TMA accumulates in the bloodstream and is exhaled, sweated, and excreted in urine, producing the characteristic persistent fishy odor of trimethylaminuria22 trimethylaminuria
TMAU, also called fish odor syndrome or fish malodor syndrome; OMIM #602079.

rs3832024 is a 2-nucleotide deletion (c.591_592del) in the FMO3 coding sequence that causes a frameshift and an immediate stop codon at amino acid position 197 (p.Cys197_Asp198delinsTer). The FMO3 protein is 532 amino acids long; the resulting truncated protein of 196 amino acids retains none of the FAD-binding or catalytic domains required for TMA N-oxygenation activity. Expression studies of similar FMO3 truncation alleles confirm no detectable functional activity toward typical FMO3 substrates33 no detectable functional activity toward typical FMO3 substrates
Yamazaki H et al. Stop codon mutations in FMO3 responsible for trimethylaminuria in a Japanese population. Mol Genet Metab, 2007. This is a complete null allele.

The Mechanism

FMO3 is the dominant TMA-oxidizing enzyme in adult human liver. It uses FAD44 FAD
flavin adenine dinucleotide — the cofactor that FMO3 uses to transfer oxygen to TMA, requiring intact FAD-binding and NADPH-binding domains in the C-terminal two-thirds of the protein and NADPH to perform N-oxygenation of TMA to TMAO. The c.591_592del deletion shifts the reading frame at codon 197, producing a stop codon that truncates the protein well before the catalytic core. Homozygous individuals carrying two D alleles produce only non-functional FMO3 fragments, leaving TMA entirely unoxidized. The disorder follows autosomal recessive inheritance55 autosomal recessive inheritance
both chromosomes must carry loss-of-function variants for full TMAU expression; single-copy carriers have sufficient residual FMO3 activity from the intact allele and do not develop the syndrome: one functional FMO3 copy is sufficient for adequate TMA clearance.

The Evidence

ClinVar classifies rs3832024 as Pathogenic66 Pathogenic
VCV000225364.15 — 6 of 6 submitters agree; review status: criteria provided, multiple submitters, no conflicts. The variant is essentially absent from European, African, South Asian, and Latino populations in gnomAD (AF = 0) but reaches a minor allele frequency of ~0.26% in East Asian populations77 ~0.26% in East Asian populations
gnomAD v4 Exomes: 0.00259 in East Asian; 0.00174 in Japanese-specific database (38KJPN 77,442 alleles), making it the most prevalent severe FMO3 loss-of-function allele in East Asian populations.

Most trimethylaminuria cases arise from compound heterozygosity88 compound heterozygosity
carrying two different loss-of-function FMO3 alleles, one on each chromosome — for example, c.591_592del on one chromosome and a different pathogenic variant on the other rather than homozygosity for a single allele. Shimizu et al. identified99 identified
Shimizu M et al. Genetic variants of FMO3 derived from Japanese subjects with trimethylaminuria. Drug Metab Pharmacokinet, 2019 multiple FMO3 frameshift and missense variants in Japanese TMAU patients, consistently demonstrating that affected individuals harbor biallelic loss-of-function combinations.

Practical Actions

The primary treatment for trimethylaminuria is dietary: restricting intake of TMA precursors (choline, lecithin, TMAO) reduces the substrate load that overwhelms absent FMO3 function. GeneReviews1010 GeneReviews
Phillips IR & Shephard EA. Primary Trimethylaminuria. GeneReviews, 2020 recommends restricting foods high in choline (eggs, liver, kidney, legumes, soya products, brassicas) and TMAO-containing seafood, and avoiding lecithin supplements. Brassicas additionally inhibit residual FMO3 activity through dietary indoles and should be restricted even if FMO3 is partially functional.

Riboflavin (vitamin B2) at pharmacological doses (30–40 mg, 3–5 times daily with food) is used to boost residual FMO3 activity in partial-loss-of-function genotypes. For complete null alleles like c.591_592del homozygosity, the benefit is theoretically limited, but riboflavin is still clinically tried. A case report by Manning et al.1111 A case report by Manning et al.
Manning NJ et al. Riboflavin-responsive trimethylaminuria. JIMD Reports, 2012 documented marked urinary TMA reduction and socially significant odor improvement with 200 mg/day riboflavin in a compound heterozygous patient, indicating meaningful residual FMO3 capacity in some biallelic combinations.

Interactions

The most important interaction for this variant is compound heterozygosity with other FMO3 loss-of-function alleles. The common mild-TMAU haplotype p.Glu158Lys + p.Glu308Gly1212 p.Glu158Lys + p.Glu308Gly
encoded by rs2266782 and rs1736557 respectively; together they reduce FMO3 activity by ~30-40% (rs2266782 + rs1736557 in cis) causes transient or mild TMAU, particularly in infancy. Individuals who carry c.591_592del (D allele, rs3832024) on one chromosome and the E158K+E308G haplotype on the other will have clinically significant TMAU because neither allele produces full enzymatic function. This is a compound heterozygous configuration worth flagging in any user who carries the D allele at rs3832024 alongside variants at rs2266782 or rs1736557.

Nutrient Interactions

choline altered_metabolism
trimethylamine N-oxide (TMAO) altered_metabolism
riboflavin increased_need

Genotype Interpretations

What each possible genotype means for this variant.

II Non-carrier Normal

Normal FMO3 — full TMA oxidation capacity

With two intact FMO3 alleles, your liver produces fully functional flavin-containing monooxygenase 3, which efficiently N-oxidizes TMA to TMAO after every choline-rich meal. Normal FMO3 function means that dietary choline, lecithin, TMAO from seafood, and other TMA precursors are cleared without odor accumulation. No dietary restriction or monitoring related to this variant is needed.

DD Homozygous (TMAU) Absent

Homozygous null — complete FMO3 absence; trimethylaminuria (fish odor syndrome)

The c.591_592del deletion at both alleles means both copies of your FMO3 gene produce only a truncated, catalytically dead protein (196 amino acids, missing the entire FAD-binding and catalytic core). The result is complete absence of hepatic TMA N-oxygenase activity. Every gram of choline in your diet that reaches the colon undergoes bacterial conversion to TMA, which is absorbed into the portal circulation and reaches the liver with no FMO3 to detoxify it.

The condition is chronic and lifelong with current management, though dietary modification can substantially reduce odor intensity. Social and psychological impact are significant — TMAU frequently causes social isolation, depression, and anxiety due to its stigmatizing nature. These psychological sequelae are a recognized part of the disease burden and should be addressed alongside metabolic management.

Management from GeneReviews (PMID 20301282) includes a multi-pronged approach: choline restriction, riboflavin supplementation (to boost any residual activity from incomplete enzyme truncation or modifier alleles), gut microbiome manipulation with intermittent antibiotics to reduce bacterial TMA production, activated charcoal to sequester TMA in the gut, and external measures (acidic soap at pH 5.5–6.5 to reduce TMA volatility from skin).

DI Carrier Carrier

Carrier of one FMO3 null allele — no personal health impact, but relevant for family planning

FMO3-related trimethylaminuria (TMAU) is an autosomal recessive condition. Carriers (one functional + one null allele) have approximately half the enzyme activity of non-carriers but are well above the threshold for clinical TMA accumulation. Under normal dietary conditions, carriers do not experience fishy odor or other TMAU symptoms.

The clinical relevance of carrier status is reproductive. If both parents carry loss-of-function FMO3 variants (whether c.591_592del or other pathogenic alleles including the common E158K+E308G haplotype that causes transient neonatal TMAU), each pregnancy has a 25% probability of producing a child with biallelic FMO3 dysfunction and clinical trimethylaminuria. This is particularly relevant in East Asian families where the D allele is most common.

Carriers may occasionally notice mild odor after very large choline loads (e.g., eating multiple eggs alongside seafood), but this is not clinically significant TMAU and requires no treatment.