rs606231425 — MMACHC

Pathogenic missense variant in the cobalamin-processing enzyme; homozygosity causes cobalamin C (cblC) disease with severe methylation and detoxification failure

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MMACHC p.Gly155Glu — A Rare but Serious Cobalamin Processing Defect

MMACHC 11 Methylmalonic aciduria and homocystinuria type C protein — the enzyme that unlocks vitamin B12 for cellular use is the gatekeeper of intracellular cobalamin metabolism. Dietary vitamin B12 arrives in cells in chemically inert forms (cyanocobalamin, hydroxocobalamin) that must be processed — decyanated and dethiolated — before they can be converted into the two active cofactors the body needs: adenosylcobalamin (for breaking down branched-chain amino acids and odd-chain fatty acids) and methylcobalamin (for the methionine synthase reaction that regenerates methionine and keeps homocysteine in check). MMACHC performs this processing step. When it fails, both downstream cofactors are depleted simultaneously, causing a dual biochemical crisis: methylmalonic acidemia and homocystinemia together.

The Mechanism

The p.Gly155Glu substitution replaces a small, flexible glycine residue at position 155 of MMACHC with the bulkier, charged glutamic acid. Position 155 lies within the TonB-like domain 22 A structural domain in MMACHC that interacts with cobalamin and facilitates its initial processing of the protein. The glycine-to-glutamate change is predicted to disrupt local protein folding and impair cobalamin binding and processing activity. In the single homozygous case reported, the child had plasma homocysteine of 123 µmol/L (normal <15 µmol/L) and methylmalonic acid of 14,424 nmol/L (normal <270 nmol/L) — a pattern consistent with complete functional loss of MMACHC.

The Evidence

The G155E variant was documented in a 2013 case series33 2013 case series
Kömhoff M et al. Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency. Pediatrics 2013 by Kömhoff et al., which reported five children with cblC deficiency presenting with the rare combination of pulmonary arterial hypertension and renal thrombotic microangiopathy. A Dutch child homozygous for c.464G>A (p.Gly155Glu) presented at 2.5 years of age and died from right ventricular failure two weeks after diagnosis despite treatment. ClinVar classifies this variant as pathogenic (RCV000148300), based on this single submission from OMIM (0-star review, reflecting a single published case report).

For heterozygous carriers, a mouse model study44 mouse model study
Moreno-Garcia MA et al. The Mmachc gene is required for pre-implantation embryogenesis in the mouse. Mol Genet Metab 2014 demonstrated that animals with one functional copy of Mmachc show 50% protein reduction accompanied by significantly elevated homocysteine and methylmalonic acid compared to wild-type littermates. Human carriers are described as clinically asymptomatic by GeneReviews, but the mouse data suggests subclinical metabolic perturbation is biologically plausible and warrants monitoring attention.

CblC disease overall occurs at approximately 1:100,000–200,000 births55 approximately 1:100,000–200,000 births. This specific G155E allele is one of many rare pathogenic MMACHC variants and is individually extremely uncommon, documented only in a single family. It is not present in gnomAD or other large population databases. Chip-based genotyping arrays (23andMe v3/v4/v5) do not include this variant; it is only detected by whole-exome or whole-genome sequencing.

Practical Actions

For heterozygous carriers: current evidence does not establish clinical disease in carriers, but the mouse model data supports a precautionary approach of ensuring optimal B12 status. Hydroxocobalamin is the preferred form because it enters the MMACHC processing pathway directly; cyanocobalamin requires additional decyanation steps. Monitoring serum homocysteine and methylmalonic acid provides an objective readout of functional cobalamin adequacy.

For homozygous individuals: this is a medical emergency requiring specialist management. The 2017 European guidelines66 2017 European guidelines
Huemer M et al. Guidelines for diagnosis and management of cblC and related remethylation disorders. J Inherit Metab Dis 2017 recommend parenteral hydroxocobalamin (1 mg/day, titrated to metabolic response) as the cornerstone of treatment, with oral betaine (250 mg/kg/day) to support remethylation via the betaine-homocysteine methyltransferase 77 BHMT — an alternative enzyme that converts betaine + homocysteine → dimethylglycine + methionine, bypassing the MMACHC-dependent pathway pathway.

Interactions

MMACHC acts upstream of two critical enzymes: methylmalonyl-CoA mutase (which requires adenosylcobalamin) and methionine synthase (MTR, rs1805087, which requires methylcobalamin). Any MMACHC dysfunction compounds with MTR and MTRR 88 MTRR rs1801394 encodes methionine synthase reductase, which reactivates MTR by remethylating its cobalamin cofactor variants that already reduce methionine synthase activity — the combined effect on methylation capacity and homocysteine levels will exceed either variant alone. Similarly, MTHFR (rs1801133) variants that reduce methylfolate supply will aggravate the homocysteine accumulation driven by impaired MMACHC function.

Nutrient Interactions

vitamin B12 impaired_conversion
folate altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-Carrier Normal

Normal MMACHC cobalamin processing function

You do not carry the p.Gly155Glu variant in the MMACHC gene. Your copy of this gene encodes a fully functional cobalamin-processing enzyme, allowing normal conversion of dietary vitamin B12 into the active cofactors (adenosylcobalamin and methylcobalamin) your cells require.

This is the common genotype — the A allele is extremely rare, present in only a handful of documented cases worldwide.

AG Carrier Carrier

Single copy of the MMACHC p.Gly155Glu pathogenic variant

As a carrier of this ultra-rare pathogenic variant, the main practical implication is reproductive: if your partner also carries an MMACHC pathogenic variant (not necessarily the same one), each pregnancy has a 25% chance of producing an affected child with cblC disease. The variant is not detectable on standard genotyping chips — only whole-exome or whole-genome sequencing reveals it. Any partner reproductive carrier screening should include MMACHC sequencing if you are planning a family.

The mouse model data supports a precautionary approach of ensuring optimal B12 status. Using hydroxocobalamin (the form that enters the MMACHC pathway directly) rather than cyanocobalamin is a low-risk optimization.

AA Homozygous Affected Homozygous

Two copies of the MMACHC p.Gly155Glu pathogenic variant — cblC disease

Without functional MMACHC enzyme, your cells cannot activate vitamin B12 regardless of dietary intake or supplementation with standard oral forms. The biochemical consequences are simultaneous elevations in methylmalonic acid (from blocked propionyl-CoA processing) and homocysteine (from blocked methionine synthase), combined with low methionine. This metabolic triad damages multiple organ systems — most critically the nervous system, retina, kidneys, and vascular endothelium.

Treatment centers on parenteral hydroxocobalamin (1 mg daily by injection) which, even though MMACHC is impaired, can partially drive cobalamin processing at saturating concentrations. Betaine supplementation provides an alternative route to lower homocysteine via BHMT. This genotype requires lifelong specialist management; outcomes are significantly better when treatment begins early.