rs3832024 — FMO3 FMO3 c.591_592del

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.