rs10925239 — MTR

MTR rs10925239 — A Deep Intronic Variant Linking Methylation to Craniofacial Development

Methionine synthase (MTR) sits at the center of the one-carbon metabolism cycle, converting homocysteine¹¹ homocysteine
Homocysteine: a sulfur-containing amino acid that is neurotoxic and cardiovascularly damaging when it accumulates; it must be recycled back to methionine or cleared via the transsulfuration pathway back into methionine using methylcobalamin (active B12) as a cofactor and 5-methylTHF (methylfolate) as the methyl donor. This reaction is critical for two reasons: it clears homocysteine and regenerates methionine, which is then converted to S-adenosylmethionine (SAM)²² S-adenosylmethionine (SAM)
SAM: the universal methyl donor for DNA methylation, histone methylation, and hundreds of other methyltransferase reactions critical to gene regulation and development, the cell's primary methyl donor for epigenetic regulation.

rs10925239 is a deep intronic variant in the MTR gene — it lies within intron sequence and does not alter the protein. Its importance comes from a 2020/2021 study linking it to reduced risk of nonsyndromic cleft lip with or without cleft palate³³ nonsyndromic cleft lip with or without cleft palate
Nonsyndromic cleft lip/palate (NSCL/P): the most common craniofacial birth defect, affecting approximately 1 in 700 births worldwide. "Nonsyndromic" means it occurs in isolation without other malformations (NSCL/P), one of the most common craniofacial birth defects.

The Mechanism

Intronic variants can influence gene function by modulating splicing efficiency, mRNA stability, or transcription factor binding at regulatory elements embedded within introns. For rs10925239, the Salamanca et al. study found that the protective G allele is associated with reduced MTR expression — meaning the G allele appears to act as a cis-regulatory⁴⁴ cis-regulatory
Cis-regulatory: affecting the expression of the gene on the same chromosome, as opposed to trans-regulatory effects on other chromosomes variant that slightly dampens MTR transcription.

This creates a counterintuitive picture: lower MTR expression is apparently protective against cleft development. The authors hypothesize this may reflect subtle changes in SAM flux — when MTR is modestly downregulated, the cell's methyl group budget may shift in ways that alter the epigenetic landscape during the critical window of palate closure. Craniofacial development is exquisitely sensitive to one-carbon metabolism status, as evidenced by the longstanding protective effect of periconceptional folate on cleft risk.

The exact molecular mechanism has not been characterized for this specific variant. It likely acts as a tag SNP⁵⁵ tag SNP
Tag SNP: a variant in linkage disequilibrium with a nearby functional variant — it marks the same haplotype block as the causal variant even if it is not itself causal in linkage disequilibrium with a nearby regulatory element or splice signal.

The Evidence

The primary evidence comes from a Chilean case-control study⁶⁶ Chilean case-control study
Salamanca C et al. Genetic variants in S-adenosyl-methionine synthesis pathway and nonsyndromic cleft lip with or without cleft palate in Chile. Pediatric Research, 2021 of 234 NSCL/P cases and 309 controls examining 18 SNPs across SAM synthesis pathway genes. Of the variants tested, three deep intronic MTR SNPs showed significant protective effects after multiple-testing correction (q-value threshold): rs10925239 (OR 0.68, p=0.0032, q=0.0192), rs10925254 (OR 0.66), and rs3768142 (OR 0.66). All three shared the same direction of effect and correlated with reduced MTR expression in database annotations.

Two contextual lines of evidence support biological plausibility. A study by Fofou-Caillierez et al.⁷⁷ Fofou-Caillierez et al.
Fofou-Caillierez MB et al. Vitamin B-12 and liver activity and expression of methionine synthase are decreased in fetuses with neural tube defects. Am J Clin Nutr, 2019 found that MTR activity, mRNA, and protein expression were all significantly reduced in fetal livers from neural tube defect cases (p=0.001, 0.016, and 0.003 respectively), and that SAM levels correlated tightly with MTR activity and B12 status — confirming that MTR expression directly governs SAM availability during fetal development. A folate pathway study⁸⁸ folate pathway study
Blanton SH et al. Folate pathway and nonsyndromic cleft lip and palate. Birth Defects Res A, 2011 by Blanton et al. found MTR association with cleft risk specifically in Hispanic populations, along with gene-gene interactions in the methionine arm of one-carbon metabolism.

Notably, a meta-analysis⁹⁹ meta-analysis
Lei W et al. Associations between MTR A2756G, MTRR A66G, and TCN2 C776G polymorphisms and risk of NSCL/P: a meta-analysis. Genet Test Mol Biomarkers, 2018 of 12 studies found the coding variant MTR A2756G (rs1805087) shows no association with NSCL/P (pooled OR 0.95, p=0.55). This null result for the coding variant, combined with the positive finding for intronic variants, suggests the NSCL/P association may be driven specifically by regulatory effects on MTR expression rather than by the enzyme's catalytic function per se.

The evidence for rs10925239 is emerging — a single case-control study, population- limited to Chile, with no independent replication yet published. SNPedia assigns a magnitude of 3.0, reflecting a documented but not yet replicated association.

Practical Actions

Because only the T allele (risk) homozygotes carry a meaningfully elevated NSCL/P association, and this is an intronic variant affecting gene expression rather than enzyme function, the practical implications are modest. Carriers of T alleles should ensure optimal B12 and folate status — active forms preferred — particularly women planning pregnancy given the craniofacial development window. Monitoring homocysteine as a functional readout of the overall methylation cycle is the most actionable and evidence-based step.

This variant does not alter MTR enzyme kinetics directly; any management approach is focused on ensuring the methylation cycle has adequate substrate supply.

Interactions

rs10925239 sits in the same gene as the better-characterized MTR A2756G variant (rs1805087). Both influence the MTR pathway, but through different mechanisms — the coding variant alters enzyme activity while rs10925239 may alter expression levels. The sister intronic variant rs10925260 has a separate (NTD) association. Upstream, MTHFR (rs1801133, rs1801131) controls the methylfolate supply that MTR depends on, and MTRR (rs1801394) reactivates oxidized B12 between MTR reaction cycles. Carriers of variants across multiple points in this triad have compounded risk for methylation insufficiency.