rs199971687 — MMAB

MMAB c.291-1G>A/T — Splice Defect at the Gateway to Adenosylcobalamin Synthesis

The MMAB gene encodes ATP:cob(I)alamin adenosyltransferase (ATR)¹¹ ATP:cob(I)alamin adenosyltransferase (ATR)
The enzyme that converts reduced cob(I)alamin to adenosylcobalamin (AdoCbl), the cofactor required by methylmalonyl-CoA mutase for propionate catabolism in mitochondria, a critical last step in the mitochondrial vitamin B12 processing pathway. When both copies of MMAB are non-functional, methylmalonyl-CoA cannot be converted to succinyl-CoA, and methylmalonic acid accumulates to toxic levels in blood, urine, and tissues — the condition known as methylmalonic aciduria cblB type²² methylmalonic aciduria cblB type
OMIM #251110; the 'cblB' designation refers to the complementation class originally defined by somatic cell fusion studies before the gene was identified. The variant at rs199971687 disrupts the splice acceptor site at the intron 3–exon 4 boundary of MMAB, destroying normal pre-mRNA processing and causing complete loss of functional ATR protein.

The Mechanism

The splice acceptor consensus sequence (AG at the 3′ end of each intron) is essential for the spliceosome to remove the intron and join exon 3 to exon 4. The c.291-1G>A and c.291-1G>T substitutions (both reported at rs199971687 on the coding/minus strand, appearing as C>T and C>A respectively on the plus strand in genome files) each destroy the invariant G of this AG dinucleotide. Functional studies on the G>A allele showed no normal mRNA transcripts at exon 4-containing sequences³³ no normal mRNA transcripts at exon 4-containing sequences
ClinVar VCV000219004, citing functional RNA analysis submitted by multiple clinical laboratories, confirming that the splice defect is complete rather than leaky.

The ATR enzyme functions as a homotrimer with three ATP-binding sites and two non-equivalent adenosylcobalamin-binding sites (Kd values of 0.55 µM and 8.4 µM). Forny et al. 2022⁴⁴ Forny et al. 2022
Forny P et al. Spectrum and characterization of bi-allelic variants in MMAB causing cblB-type methylmalonic aciduria. Hum Genet, 2022 showed that the propionate incorporation ratio — the ratio of propionate metabolism with and without added hydroxocobalamin — predicts both clinical cobalamin responsiveness and age of disease onset. Splice-site variants that eliminate mRNA entirely effectively produce a null allele; disease onset and responsiveness depends on what the second allele produces.

The Evidence

The two pathogenic alleles at this locus are both classified as Pathogenic in ClinVar: the G>A allele (ClinVar VCV000219004) carries criteria-provided review status with nine submitting laboratories including LabCorp, Invitae, Mayo Clinic, Baylor Genetics, and GeneDx. The G>T allele (ClinVar VCV001173991) was documented by the Baumgartner laboratory at the University Children's Hospital Zurich and reported in the Forny et al. 2022 case series.

Lerner-Ellis et al. 2006⁵⁵ Lerner-Ellis et al. 2006
Lerner-Ellis JP et al. Mutation and biochemical analysis of patients belonging to the cblB complementation class of vitamin B12-dependent methylmalonic aciduria. Mol Genet Metab, 2006 sequenced MMAB in 35 cblB patients and identified 19 mutations including four splice-site variants. The most common European pathogenic allele is p.(Arg186Trp) at c.556C>T, accounting for 29–33% of European cblB alleles; rs199971687 is a rare allele that has been observed primarily in individual case reports.

cblB-type MMA has a birth prevalence of approximately 1 in 159,614 in the US⁶⁶ 1 in 159,614 in the US
Manoli I et al., GeneReviews, Isolated Methylmalonic Acidemia, NCBI Bookshelf NBK1231, 2022, with higher rates in the Middle East, North Africa, and parts of East Asia due to founder effects and consanguinity. This makes obligate carriers — individuals with one loss-of-function MMAB allele — far more common than affected individuals, with an estimated carrier frequency of roughly 1 in 200 in European populations.

Practical Actions

For carriers (CT genotype): Carriers have one functional MMAB allele producing sufficient ATR enzyme to handle normal propionate metabolism. No metabolic symptoms occur in heterozygous carriers, and no dietary or supplementation changes are needed for the carrier's own health. The clinical significance of carrier status is entirely in the domain of family planning: if both parents carry a pathogenic MMAB allele, each pregnancy carries a 25% risk of producing an affected child.

For affected individuals (TT or homozygous/compound heterozygous for any two MMAB loss-of-function alleles): Treatment depends on cobalamin responsiveness. Approximately 40–50% of cblB patients show at least partial responsiveness to pharmacological-dose hydroxocobalamin⁷⁷ hydroxocobalamin
The natural, non-cyano form of B12; preferred over cyanocobalamin for cobalamin metabolism disorders because it is more efficiently retained and distributed to mitochondria. Standard assessment involves 1 mg hydroxocobalamin intramuscularly daily for 3–5 days; a reduction in urinary methylmalonic acid by >50% defines responsiveness. All cblB patients, regardless of responsiveness, require protein-restricted diet, emergency metabolic protocols during illness, and regular monitoring of methylmalonic acid, ammonia, renal function, and neurological status.

Interactions

MMAB loss-of-function sits at a node where several B12 processing pathways converge. AdoCbl is the exclusive cofactor for methylmalonyl-CoA mutase; without it, propionate catabolism halts regardless of circulating B12 levels. The downstream biochemical consequences — elevated propionylcarnitine, methylmalonic acid, and homocysteine — connect MMAB deficiency to the folate-methylation cycle. Carriers of common MTHFR variants (rs1801133) already have moderately elevated homocysteine; an MMAB carrier parent in a family with known cblB history should be aware of this compounding possibility in an affected child who has biallelic MMAB loss.

For genetic counseling purposes, rs199971687 should be interpreted in the context of the second MMAB allele. Many compound heterozygous cblB patients carry this splice-site allele on one chromosome and a missense allele (such as p.Arg186Trp) on the other. In those combinations, cobalamin responsiveness is determined by which allele retains more residual function — typically the missense allele.