rs199971687 — MMAB

Pathogenic splice acceptor variant in MMAB that abolishes adenosylcobalamin synthesis, causing methylmalonic aciduria cblB type when two loss-of-function alleles are inherited

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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.

Nutrient Interactions

vitamin B12 (cobalamin) impaired_conversion

Genotype Interpretations

What each possible genotype means for this variant.

CC Non-carrier Normal

Two normal MMAB copies — standard adenosylcobalamin synthesis

You carry two copies of the reference C allele at rs199971687 in MMAB, meaning both of your splice acceptor sites at the intron 3–exon 4 boundary are intact. Your MMAB gene produces normal ATP:cob(I)alamin adenosyltransferase protein, and your mitochondria can convert vitamin B12 to adenosylcobalamin at normal capacity. This is by far the most common genotype — over 99.98% of people across all populations carry two reference alleles at this position.

CT Carrier Carrier

One pathogenic MMAB splice variant — carrier for cblB methylmalonic aciduria

The splice acceptor site at c.291-1 is the invariant AG dinucleotide at the 3′ end of intron 3. The G>A change (coding strand, appearing as C>T in plus-strand genome files) destroys this critical signal. Functional studies confirmed that no normal exon 4-containing mRNA is produced from the affected allele, making this effectively a null allele. The two-copy threshold of autosomal recessive inheritance means one functional allele is sufficient to maintain enzyme activity at 30–50% of normal, which is enough for clinical phenotypic normality.

Partner cascade testing is the key clinical action for carriers. If a partner is also found to carry a pathogenic MMAB variant, the couple should be offered reproductive genetic counseling including discussion of preimplantation genetic testing (PGT) or prenatal diagnosis.

TT Homozygous Homozygous

Two copies of pathogenic MMAB splice variant — consistent with cblB methylmalonic aciduria

cblB methylmalonic aciduria (OMIM #251110) presents in one of two patterns depending on the specific MMAB alleles involved. The classic early-onset, non-responsive form occurs with null alleles on both chromosomes and typically presents in the first days to weeks of life with lethargy, vomiting, tachypnoea, and metabolic acidosis triggered by protein-containing feeds. Elevated methylmalonic acid (often >1,000 µmol/L; normal <0.4 µmol/L), elevated propionylcarnitine (C3), and hyperammonaemia are the hallmark biochemical findings.

A minority of cblB patients with at least one allele retaining partial ATR activity show later onset and cobalamin responsiveness: pharmacological-dose hydroxocobalamin (1 mg IM daily for 3–5 days) reduces urinary methylmalonic acid by more than 50%, permitting less stringent dietary management. For splice-site null alleles like rs199971687, cobalamin responsiveness depends entirely on what the second allele produces.

Long-term complications in cblB include chronic kidney disease, optic neuropathy, metabolic stroke, and neurodevelopmental delay — all related to accumulated toxic intermediates and energy deficit in high-demand tissues. Affected individuals need lifelong specialist metabolic follow-up.