rs10925260 — MTR

Intronic MTR variant associated with altered methionine synthase expression and neural tube defect risk

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MTR rs10925260 — An Intronic Variant in the Methylation Cycle Core

Methionine synthase (MTR), also known as MS, carries out one of the most important reactions in human metabolism: it converts homocysteine11 homocysteine
Homocysteine: a potentially toxic amino acid that builds up when the methylation cycle is impaired back into methionine using methylcobalamin (active B12) as a cofactor and 5-methylTHF (methylfolate) as the methyl donor. This single reaction links folate metabolism and B12 status, and when it falters, homocysteine rises and methylation capacity falls.

rs10925260 is an intronic variant in the MTR gene — it does not change the protein sequence directly. Intronic variants can still influence gene function by altering splicing efficiency, mRNA stability, or regulatory element binding, but the exact mechanism for this particular variant has not been characterized at the molecular level.

The Mechanism

Because rs10925260 lies within an intron (c.2677-335A>C in one transcript, 22 c.2677-335A>C notation: 335 base pairs upstream of exon boundary, on the forward strand placing it 335 base pairs upstream of an exon boundary), its most likely functional role is as a tag SNP33 tag SNP
Tag SNP: a variant in linkage disequilibrium with a nearby functional variant, acting as a proxy marker for that variant's effect in linkage disequilibrium with a nearby functional variant, or a subtle regulatory element affecting MTR expression levels. Ensembl VEP scores this variant with a CADD score44 CADD score
CADD: Combined Annotation Dependent Depletion score — higher scores indicate greater predicted deleteriousness; 0.38 is very low of 0.38 and GERP conservation of −1.84, both suggesting minimal evolutionary constraint. This is consistent with a common regulatory tag SNP rather than a strongly functional coding change.

The Evidence

The most direct evidence for rs10925260 comes from a replication study55 replication study
Pangilinan F et al. Replication and exploratory analysis of 24 candidate risk polymorphisms for neural tube defects. BMC Med Genet, 2014 by Pangilinan and colleagues, who tested 24 candidate SNPs in folate-pathway genes across independent cohorts (530 UK NTD trios and 190 New York State cases with 941 controls). Of the 24 SNPs tested, MTR rs10925260 was one of only two that reached nominal statistical significance for isolated neural tube defects (along with ADA rs452159). The authors note this association did not survive correction for multiple comparisons across all 24 tests, and they call for additional independent replication.

Neural tube defect risk is one of the most folate-sensitive outcomes in human biology — the MTR pathway is directly implicated because adequate methylation requires both B12-dependent MTR activity and upstream methylfolate supply from MTHFR. Studies of the well-characterized MTR coding variant A2756G66 A2756G
Li et al. MTR A2756G associated with increased NTD risk in Chinese population. 2015 (rs1805087) show a modest association with NTD risk (OR 1.45, 95% CI 1.06–1.98), providing biological plausibility for the rs10925260 finding via a shared pathway.

The broader MTR gene context also links B12 metabolism to cardiovascular risk77 cardiovascular risk
Klerk M et al. MTR 2756A>G and CHD risk, 2003, homocysteine elevation, and one-carbon metabolism efficiency — all traits where subtle differences in MTR expression could matter.

Practical Implications

Given the emerging and unconfirmed evidence, this variant should not drive supplementation decisions on its own. However, carriers of one or two A alleles (AA or AC genotype) can reasonably prioritize active B12 forms and methylfolate as a precautionary measure, especially women of childbearing age given the NTD association. The form of B12 matters: methylcobalamin and hydroxocobalamin bypass the conversion steps that require MTR to be fully functional, whereas cyanocobalamin still requires enzymatic processing.

Interactions

rs10925260 sits in the same gene as the better-characterized MTR A2756G variant (rs1805087). If you carry variants at both loci, the combined effect on MTR expression and function is unknown but potentially additive. The MTR enzyme works in tandem with MTRR (rs1801394), which reactivates oxidized B12 after each MTR reaction cycle, and upstream MTHFR (rs1801133 C677T, rs1801131 A1298C), which supplies the methylfolate substrate. Weakness at multiple points in this system compounds the impact on homocysteine clearance and methylation capacity.

Nutrient Interactions

vitamin B12 increased_need
folate altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

CC Common Homozygous Normal

Two common C alleles — normal MTR variant status

You carry two copies of the C allele, the most common genotype in most global populations (approximately 31% globally, higher in European and South Asian populations). Based on the limited available evidence for rs10925260, this genotype is not associated with elevated neural tube defect risk or altered B12/folate metabolism.

Standard dietary guidelines for B12 and folate apply.

AC Heterozygous Intermediate

One copy of each allele — intermediate status

You carry one A allele and one C allele at rs10925260. This is the most common genotype globally (approximately 49% of people). Heterozygotes are expected to have an intermediate effect compared to either homozygote, though with an emerging-level variant like this, the heterozygous effect has not been specifically quantified.

As a precautionary measure, ensuring adequate B12 and folate intake is reasonable, particularly around pregnancy.

AA Minor Allele Homozygous High Risk

Two copies of the rare A allele — associated with NTD risk

The A allele is the GRCh38 reference allele but is less common globally (allele frequency ~0.44). AA homozygotes represent approximately 19% of the global population but a higher proportion in African populations (~28%). The functional mechanism is unknown; the variant likely acts as a tag SNP for a nearby regulatory element affecting MTR expression. Evidence is limited to one replication study (Pangilinan et al. 2014, PMID 25293959), which found nominal significance for NTD risk without multiple-testing correction. Clinical action on this finding alone is not warranted, but it reinforces the importance of B12 and folate adequacy.