rs1979277 — SHMT1 C1420T

SHMT1 C1420T — A Folate Metabolism Variant with Complex Health Effects

The SHMT1 gene encodes serine hydroxymethyltransferase 1, a pyridoxal phosphate (vitamin B6)-dependent enzyme¹¹ pyridoxal phosphate (vitamin B6)-dependent enzyme
SHMT1 requires vitamin B6 as a cofactor that sits at a critical junction in one-carbon metabolism²² one-carbon metabolism
the folate cycle that provides methyl groups for DNA synthesis, repair, and methylation. SHMT1 converts serine and tetrahydrofolate into glycine and 5,10-methylenetetrahydrofolate, supplying one-carbon units for thymidylate synthesis (DNA building blocks) and methylation reactions. The C1420T variant causes a leucine-to-phenylalanine substitution at position 474 of the protein, altering its cellular localization and affecting how efficiently the enzyme channels one-carbon units through different metabolic pathways.

The Mechanism

The Leu474Phe amino acid change affects the enzyme's cellular distribution³³ affects the enzyme's cellular distribution
The T allele alters SHMT1 localization within cells, reducing availability of 5,10-methylenetetrahydrofolate rather than simply destroying its activity. SHMT1 normally shuttles between the cytoplasm and nucleus during DNA replication, providing one-carbon units directly where they're needed. The 1420T variant appears to disrupt this trafficking, causing the enzyme to favor certain metabolic routes over others. Specifically, it may reduce the supply of methylenetetrahydrofolate⁴⁴ reduce the supply of methylenetetrahydrofolate
substrate required by the MTHFR enzyme that converts it to methylfolate for homocysteine remethylation. This creates a metabolic bottleneck: less substrate available for MTHFR, potentially leading to elevated homocysteine if folate intake is marginal.

Intriguingly, individuals with the CC genotype have lower plasma and red blood cell folate levels⁵⁵ individuals with the CC genotype have lower plasma and red blood cell folate levels
Study of neural tube defect families found significantly decreased folate in CC carriers compared to T allele carriers — the opposite of what you might expect given the T allele's functional changes. This paradox likely reflects a compensatory redistribution: the T variant shifts folate derivatives toward different storage forms or compartments rather than simply depleting them. The clinical consequences depend on which metabolic pathway matters most for a given condition.

The Evidence

The most robust data come from cancer association studies⁶⁶ cancer association studies
Multiple meta-analyses with tens of thousands of participants. A meta-analysis of 7,309 lymphoma patients⁷⁷ meta-analysis of 7,309 lymphoma patients
3,232 cases and 4,077 controls across eight studies found the TT genotype modestly increases non-Hodgkin lymphoma risk (OR = 1.18), with borderline significance. The association is stronger for the T allele in general (OR = 1.09, p = 0.025), suggesting a dose-dependent effect. Mechanisms likely involve impaired DNA synthesis or methylation during rapid immune cell proliferation.

Conversely, a meta-analysis of 31,405 solid tumor cases⁸⁸ meta-analysis of 31,405 solid tumor cases
14,409 cases and 16,996 controls from 23 studies revealed the TT genotype protects against breast cancer in Asian populations (OR = 0.79, p = 0.003), though not in Caucasians. A similar protective effect appears for rectal cancer⁹⁹ rectal cancer
Study of 476 rectal cancer patients in Hungary, where TT carriers had 43% lower risk (OR = 0.57). For acute lymphoblastic leukemia¹⁰¹⁰ acute lymphoblastic leukemia
Univariate analysis in adults, the TT genotype conferred a striking 3.3-fold risk reduction (OR = 0.31). These protective effects may arise from altered folate partitioning that reduces availability of nucleotides for rapidly dividing cancer cells.

The cardiovascular story involves gene-gene interactions¹¹¹¹ gene-gene interactions
SHMT1 and MTHFR polymorphisms interact to influence CVD risk. In the Nurses' Health Study, women carrying both SHMT1 TT and MTHFR 677 CT genotypes faced 4.3-fold increased cardiovascular disease risk compared to women with CC for both variants. The mechanism: reduced substrate (5,10-methylenetetrahydrofolate) from SHMT1 TT compounds the impaired enzyme activity from MTHFR 677T, creating a severe bottleneck in homocysteine remethylation. Elevated homocysteine and C-reactive protein together predict worse cardiovascular outcomes¹²¹² Elevated homocysteine and C-reactive protein together predict worse cardiovascular outcomes
Prospective study of 291 stroke patients over 5 years, with combined high levels raising risk 4.67-fold.

Practical Implications

If you carry one or two T alleles, your folate metabolism is functional but may be less efficient at certain steps, particularly the conversion of folate intermediates into methylfolate for homocysteine metabolism. The clinical relevance depends heavily on context — your folate intake, the status of other folate-cycle genes (especially MTHFR), and which tissues are most metabolically active.

For cardiovascular protection¹³¹³ cardiovascular protection
SHMT1 interacts with MTHFR to influence heart disease risk, prioritize methylfolate over synthetic folic acid, especially if you also carry MTHFR 677T or 1298C variants. The SHMT1-MTHFR interaction can significantly elevate homocysteine, an independent risk factor for atherosclerosis. Consider periodic homocysteine testing (ideal range: <10 μmol/L) to monitor whether your folate metabolism is keeping up with demand.

The cancer associations are complex and context-dependent. The T allele may increase risk for blood cancers involving rapid immune cell division, but appears protective against some solid tumors. This isn't a call to avoid or embrace the variant — it's fixed in your DNA — but rather a reminder that optimal folate status matters. Adequate B vitamin intake supports proper DNA synthesis and repair regardless of genotype.

Interactions

SHMT1 C1420T interacts most notably with MTHFR C677T (rs1801133) and A1298C (rs1801131). When SHMT1 TT reduces the supply of 5,10-methylenetetrahydrofolate, and MTHFR 677T reduces the enzyme's ability to convert that substrate, the combined effect significantly impairs methylfolate production and homocysteine remethylation. This gene-gene interaction substantially increases cardiovascular disease risk beyond either variant alone, particularly in the context of marginal folate intake. Individuals with both SHMT1 TT and MTHFR 677 CT or TT genotypes should prioritize methylfolate supplementation and monitor homocysteine levels.

SHMT1 also functions in the same pathway as SLC19A1 G80A (RFC1, rs1051266), the main folate transporter into cells, and MTRR A66G (rs1801394), which recycles methionine synthase. Variants in these genes can compound SHMT1-related inefficiencies by further limiting folate availability or homocysteine remethylation capacity.