rs369296618 — MMAB

MMAB Q234* — A Nonsense Variant at the Final Step of Adenosylcobalamin Synthesis

The MMAB gene encodes ATP:cob(I)alamin adenosyltransferase (ATR)¹¹ ATP:cob(I)alamin adenosyltransferase (ATR)
The enzyme that attaches an adenosyl group to reduced cobalamin, converting it into adenosylcobalamin — the active B12 cofactor required by methylmalonyl-CoA mutase in the mitochondria, the final enzyme in the pathway that converts dietary vitamin B12 into its active mitochondrial form, adenosylcobalamin (AdoCbl). Without AdoCbl, methylmalonyl-CoA mutase²² methylmalonyl-CoA mutase
The mitochondrial enzyme that converts methylmalonyl-CoA to succinyl-CoA; it cannot function without its AdoCbl cofactor, causing methylmalonate to accumulate stalls, causing toxic accumulation of methylmalonate and propionate in blood and tissues. This SNP — rs369296618, c.700C>T, p.Gln234Ter — introduces a premature stop codon at amino acid 234 of the 250-amino-acid MMAB protein. Because it falls in the final (terminal) exon, the truncated transcript may partly escape nonsense-mediated decay (NMD)³³ nonsense-mediated decay (NMD)
A cellular surveillance mechanism that degrades mRNAs with premature stop codons more than ~50 nucleotides upstream of the final exon junction; terminal-exon stop codons often escape, producing a truncated but partially functional protein, leaving behind a shortened protein with residual enzymatic activity in some carriers.

The Mechanism

ATR is a homotrimer that catalyses the final adenosylation step: cob(I)alamin + ATP → adenosylcobalamin + pyrophosphate. The Q234* truncation removes 16 amino acids from the C-terminus of the protein. Because the stop codon is within the terminal exon, the abnormal mRNA may not be fully degraded by NMD, producing some truncated ATR protein. This distinguishes Q234* from early-truncating alleles (e.g., p.Arg186Trp affects the active-site core) — the terminal location preserves some structural integrity, which is why a subset of biallelic Q234* individuals retain partial B12 responsiveness. Forny et al. 2022⁴⁴ Forny et al. 2022
Human Genetics; 97 individuals with bi-allelic MMAB variants confirmed c.700C>T as the most frequent truncating MMAB allele, appearing in 14 patients across the cohort. Disease onset in biallelic carriers ranged from 2 days to 6.5 years of age, reflecting the partial residual activity conferred by terminal-exon escape from NMD.

The Evidence

Manoli et al. (GeneReviews, updated 2022)⁵⁵ Manoli et al. (GeneReviews, updated 2022)
Isolated Methylmalonic Acidemia documents that MMAB variants cause cblB-type methylmalonic aciduria (MMA), accounting for approximately 12% of all isolated MMA cases. The condition follows strict autosomal recessive inheritance — biallelic loss of MMAB function causes accumulation of methylmalonic acid in plasma and urine, with clinical presentations ranging from neonatal hyperammonemic crisis to late-onset renal and neurological complications. Heterozygous carriers are clinically silent and do not require treatment.

ClinVar (VCV000203820) classifies rs369296618 as Pathogenic with two-star review status ("criteria provided, multiple submitters, no conflicts"), supported by eight independent laboratory submissions including Baylor Genetics, Natera, and Victorian Clinical Genetics Services, all confirming the variant in affected individuals in homozygous or compound heterozygous states.

For biallelic disease: hydroxocobalamin therapy (1 mg IM, 1–3 × weekly) is the first-line intervention for B12-responsive cases, alongside dietary protein restriction targeting propiogenic amino acids and supplemental L-carnitine (50–100 mg/kg/day) to maintain plasma carnitine levels and facilitate excretion of propionylcarnitine.

Practical Actions

Heterozygous carriers (AG genotype, ~1 in 2,500 Europeans) have one functional MMAB copy and produce sufficient AdoCbl — no dietary or supplement intervention is needed for the carrier themselves. The clinical relevance is reproductive: if both reproductive partners carry a pathogenic MMAB allele, each pregnancy carries a 25% chance of producing a biallelic child with cblB-type MMA. Newborn screening (tandem mass spectrometry for elevated propionylcarnitine) identifies affected neonates before the first metabolic crisis.

Homozygous AA (effectively impossible in the general population given q ≈ 0.00018) or compound heterozygous states (one copy of this allele + one copy of a different MMAB pathogenic variant such as rs199971687) cause clinical MMA. Management is specialist-led: high-dose hydroxocobalamin, protein restriction, and carnitine supplementation.

Interactions

Compound heterozygosity between rs369296618 and other pathogenic MMAB alleles (particularly rs199971687, a splice-acceptor variant) causes cblB-type MMA with the same clinical spectrum as biallelic state. The Q234* allele specifically may retain partial enzymatic activity, meaning compound heterozygotes carrying Q234* on one allele may show better hydroxocobalamin responsiveness than those with two early-truncating variants. This interaction is well-established in the cblB literature and should inform counselling when both MMAB variants are identified in a couple.