rs2275565 — MTR IVS (intronic)

MTR rs2275565 — A Second Methionine Synthase Signal

This SNP sits in an intron of MTR, the gene encoding methionine synthase — the enzyme that uses vitamin B12 as a cofactor to remethylate homocysteine back to methionine. Unlike the well-known missense variant rs1805087 (MTR A2756G / D919G), rs2275565 does not change the amino acid sequence of the enzyme. Instead, it appears to act as a regulatory variant that modestly shifts MTR expression or splicing and, as a consequence, influences how efficiently the one-carbon cycle runs under B12 and folate stress.

The Mechanism

rs2275565 is a G>T change on the plus strand at chr1:236885376 (GRCh38), located within an MTR intron across multiple transcript variants ¹¹ The variant is annotated as an intron variant by Ensembl VEP and as benign by ClinVar, but observational studies repeatedly link the T allele to higher plasma homocysteine. Because it is intronic it has no direct effect on the methionine synthase protein sequence. The most likely mechanism is a small effect on transcription, splicing, or mRNA stability that reduces enzyme abundance at the margin — enough to matter when B12 or folate supply is limited, but too subtle to show up in well-nourished cohorts.

The Folate/B12 Pathway Context

MTR sits at the convergence of the folate and B12 cycles. It takes a methyl group from 5-methyltetrahydrofolate (produced by MTHFR) and transfers it to homocysteine via a methylcobalamin intermediate. When MTR output drops, two things happen at once: homocysteine builds up, and methylfolate accumulates unusably — the so-called "methyl-folate trap" ²² Methylfolate can only donate its methyl group through MTR; when MTR is slow, methylfolate traps the folate pool in an unusable form. Because rs2275565 is a quantitative tweak rather than a missense hit, its phenotype is most visible when other pressures are in play: low B12 intake, competing MTHFR or MTRR variants, oxidative stress, or pregnancy.

The Evidence

The strongest recent signal comes from a Chinese case-control study³³ Chinese case-control study
Liu et al. Association of MTR gene polymorphisms with non-syndromic congenital heart disease. Scientific Reports, 2023 of 620 infants with non-syndromic congenital heart disease versus 620 controls. The TT genotype was associated with a roughly 5-fold increased risk of CHD (aOR 4.93, 95% CI 1.93–12.58), and the heterozygous GT genotype with a ~1.5-fold increase. This fits the broader pattern in which maternal one-carbon metabolism disturbances raise developmental risk for neural tube and cardiac defects.

Homocysteine findings are more mixed. The NHLBI Family Heart Study⁴⁴ NHLBI Family Heart Study
Jacques et al. Effects of MTR and MTRR polymorphisms on total plasma homocysteine, Atherosclerosis 2003 (n=677) found no significant effect of MTR variants on fasting plasma homocysteine but a trend toward higher post-methionine-load homocysteine in carriers. Overall the evidence level is moderate: the biological direction is consistent (T allele → more stress on the B12/folate cycle), but effect sizes in well-nourished populations are small and not all studies replicate.

Practical Actions

For T allele carriers, the practical move is to keep B12 status unambiguously generous — this is the cofactor MTR can't do without. Methylcobalamin or hydroxocobalamin are preferable to cyanocobalamin because they bypass a reduction step. Pairing with methylfolate (rather than synthetic folic acid) is the standard complement when there are also MTHFR variants present. Periodic homocysteine testing gives an objective readout of whether the cycle is running cleanly.

Interactions

rs2275565 is most meaningful when stacked with other one-carbon variants: rs1805087 (MTR D919G, the missense MTR variant), rs1801394 (MTRR A66G, which handles B12 reactivation), and rs1801133 (MTHFR C677T, the upstream methylfolate producer). A person heterozygous at rs2275565 alone is typically fine; a person with MTHFR TT plus one or both MTR hits benefits from more deliberate B12 and methylfolate support.