MTRR K350R — A Second B12 Recycling Variant
Methionine synthase reductase (MTRR) is the enzyme that keeps the methylation
cycle running by reactivating methionine synthase (MTR) after it becomes
oxidized. MTR uses
methylcobalamin11 methylcobalamin
The methyl-carrying form of vitamin B12 that donates a methyl group to convert homocysteine → methionine
to convert homocysteine into methionine, but that reaction periodically
inactivates B12. MTRR steps in to restore it. The rs162036 variant (K350R)
introduces a lysine-to-arginine change at position 350 of the MTRR protein —
a second functionally relevant variant in MTRR distinct from the well-known
A66G (rs1801394).
The Mechanism
Position 350 of MTRR sits within the
reductase catalytic domain22 reductase catalytic domain
The domain responsible for electron transfer that reduces oxidized cobalamin back to the active methylcobalamin form
that performs reductive methylation of MTR's cobalamin cofactor. The K350R
substitution changes a positively charged lysine to a similarly charged arginine,
which is why SIFT scores it as tolerated and PolyPhen as benign at the
sequence-prediction level. Nonetheless, population and clinical data suggest
the change meaningfully affects B12 recycling efficiency in ways that influence
real-world outcomes — particularly the response to folate and B12 supplementation.
ClinVar classifies this variant as predominantly benign for cobalamin metabolism
disorders, though one submission records uncertain significance.
The Evidence
A California registry study by
Shaw et al.33 Shaw et al.
Shaw GM et al. 118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects. BMC Med Genet, 2009
(259 spina bifida cases, 359 controls) found rs162036 associated with a
threefold increase in spina bifida risk (OR=3.0, 95% CI 1.5–5.9). This is a
larger effect than many better-known folate-pathway variants, though the
confidence interval is wide, reflecting the modest sample.
In patients with
hyperhomocysteinaemia44 hyperhomocysteinaemia
Elevated blood homocysteine — a cardiovascular and neurodevelopmental risk factor correctable with B-vitamin supplementation,
Du et al.55 Du et al.
Du B et al. Genetic polymorphisms of key enzymes in folate metabolism affect the efficacy of folate therapy. Br J Nutr, 2018
found that the AG and AG+GG genotypes were associated with reduced efficacy
of standard folic acid therapy (P<0.05). A follow-up study by
Li et al.66 Li et al.
Li D et al. Association of genetic and epigenetic variants in one-carbon metabolism with folate treatment response. Eur J Clin Nutr, 2020
confirmed this association (P=0.048) and demonstrated that DNA methylation at
the MTRR locus mediated approximately 41% of the genotype's effect on folate
treatment response, linking the genetic variant to epigenetic modification.
A targeted next-generation sequencing study by
Liu et al.77 Liu et al.
Liu X et al. Targeted NGS identifies novel sequence variations associated with nonobstructive azoospermia. Med Sci Monit, 2019
reported an odds ratio of 3.686 (95% CI 1.228–11.066) for non-obstructive
azoospermia — though the sample was small (34 cases, 40 controls) and a
different Chinese cohort found no association, making the fertility signal
preliminary88 preliminary
An earlier larger Irish study by O'Leary et al. (PMID 15979034, n=470 cases, 476 controls) found no significant NTD association with K350R, illustrating population heterogeneity.
Practical Actions
The clearest clinical implication of the G allele is reduced responsiveness to standard folic acid supplementation. Where someone with an AA genotype may achieve adequate homocysteine lowering from folic acid alone, G-allele carriers — especially GG homozygotes — appear to respond better when active folate forms (5-methyltetrahydrofolate) are used directly, bypassing the impaired enzymatic recycling step.
Hydroxocobalamin is the preferred B12 form because it can be enzymatically converted to both methylcobalamin (the MTR cofactor) and adenosylcobalamin (the mitochondrial form), giving MTRR more substrate to work with despite reduced reactivation efficiency.
Monitoring serum homocysteine is particularly informative here: persistently elevated homocysteine despite supplementation is a functional marker that B12 recycling is inadequate, and can guide dose adjustments or form switches.
Interactions
MTRR K350R (rs162036) acts alongside the MTRR A66G variant (rs1801394) in the same enzyme. Both reduce B12 recycling efficiency, but at different structural positions. Carrying risk alleles at both sites compounds the functional deficit. Combined impairment in MTRR B12 recycling is further magnified when MTHFR C677T (rs1801133) is also present — the methylation cycle then faces reduced folate supply (MTHFR) and reduced B12 reactivation (MTRR), a combination associated with the highest observed homocysteine elevations. MTR A2756G (rs1805087), which directly encodes methionine synthase, forms a third point of intersection in the same B12-dependent reaction.