rs1979277
badMag 3.5This is a variant in the SHMT1 gene that changes a leucine to an phenylalanine.
Key Literature Trait Associations
Folate-Mediated One-Carbon Metabolism
The SHMT1 C1420T variant (rs1979277) is a missense polymorphism (Leu474Phe) in cytoplasmic serine hydroxymethyltransferase, which provides one-carbon units for DNA synthesis and methylation by converting serine to glycine. The A allele may alter the balance between thymidylate synthesis and homocysteine remethylation. Parental carrier status has been associated with increased neural tube defect risk in offspring.
Neural tube defects
A family-based case-control study of 924 subjects (124 NTD case-parent trios plus 184 control-parent trios) in South India found that the paternal TT genotype was associated with both anencephaly (p=0.018) and spina bifida (p=0.022) in offspring, and a maternal CT × paternal TT interaction further elevated fetal NTD risk (p=0.021). The T allele reduces SHMT1 activity, potentially limiting folate-mediated thymidylate synthesis during neural tube closure, complementing the well-established MTHFR 677T NTD association. Evidence is currently limited to a single study with a modest sample size.
Fetal growth restriction
A Russian case-control study (122 FGR cases, 243 controls) found that the maternal T allele of rs1979277 was significantly associated with fetal growth restriction across multiple inheritance models: allelic OR=1.67 (95% CI 1.20–2.33, p<0.01), dominant OR=1.81 (p=0.01), and recessive OR=2.34 (p=0.01). The proposed mechanism is that reduced maternal SHMT1 activity impairs placental folate utilization, compromising fetal growth. This association is based on a single study and requires replication in larger, multi-ethnic cohorts.
Non-Hodgkin lymphoma
A meta-analysis of 8 studies (3,232 NHL cases, 4,077 controls) found that the T allele of SHMT1 C1420T was significantly associated with increased NHL risk in the allelic comparison (T vs. C: OR=1.09, 95% CI 1.01–1.17). Borderline significant associations were also found under homozygote (TT vs. CC: OR=1.18) and dominant models. An earlier UK case-control study found no significant associations, suggesting possible heterogeneity across populations. The effect magnitude is modest and most studies were small; larger confirmatory studies are needed.
Colorectal cancer
A meta-analysis of 15 Caucasian studies (5,043 cases / 6,311 controls) found no overall association between the C1420T polymorphism and colorectal cancer risk, but revealed significant geographic heterogeneity: European populations showed modestly increased susceptibility (OR 1.11–1.17) while American populations showed a protective trend (OR 0.86–0.87; interaction p=0.004). A broader meta-analysis of 19 studies (21,640 participants) similarly found no overall cancer effect but identified protective associations in colorectal cancer and Asian subgroups. A Hungarian case-control study (n=~950) found the T allele was associated with significantly reduced rectal cancer risk (OR=0.57, 95% CI 0.36–0.89), with a gene-dosage effect, though no association with colon cancer was seen. Overall, th...
Prostate cancer
A meta-analysis pooling two studies (2,689 cases, 4,110 controls) found weak evidence that the T allele (dominant model) was associated with increased prostate cancer risk (OR=1.11, 95% CI 1.00–1.22; p=0.05), with subjects predominantly Caucasian. A subsequent review of folate/B12 pathways in prostate cancer confirmed this borderline association. The effect is modest and barely reaches nominal significance; no large GWAS has replicated this finding, so evidence remains low.
Acute lymphoblastic leukemia
A systematic review and meta-analysis of 9 studies (2,971 ALL cases, 3,521 controls) found no significant overall association between rs1979277 and ALL risk across dominant (OR=0.84, p=0.57), recessive (OR=0.81, p=0.50), and allelic (OR=0.84, p=0.48) models in Caucasian and Asian pediatric populations. An earlier Iranian case-control study (n=240) reported significantly increased ALL risk with rs1979277 (p<0.05), but this was not replicated in the pooled analysis. Overall, the weight of current evidence does not support a meaningful association with ALL.
▶ClinVar annotation
▶Research that mentions this SNP (5)
▶Association of main folate metabolic pathway gene polymorphisms with neural tube defects in Han population of Northern ChinaAssociationN=321Yulian Fang et al.(2018)· Child's Nervous System
A case-control study of 152 NTD patients and 169 controls in Han Chinese population identified three folate metabolism pathway SNPs associated with neural tube defects: rs2236225 in MTHFD1 (allele A, OR=1.500; AA genotype OR=2.862), rs1801133 in MTHFR (allele T, OR=1.552; TT genotype OR=2.344), and rs1801394 in MTRR (allele G, OR=1.533; GG genotype OR=2.355). The study demonstrates genetic variation in folate metabolism significantly affects NTD susceptibility.
▶MTHFR rs2274976 polymorphism is a risk marker for nonsyndromic cleft lip with or without cleft palate in the Brazilian populationAssociationN=1,712Sibele Nascimento de Aquino et al.(2014)· Birth Defects Research Part A: Clinical and Molecular Teratology
Case-control study of 501 young stroke patients and 1,211 controls examining 58 polymorphisms in 17 genes involved in methionine metabolism. Multiple logistic regression identified four independent risk factors for early-onset ischaemic stroke: rs10037045 BHMT (OR 1.38, p=0.033), rs682985 BHMT2 (OR 1.46, p=0.017), rs1051319 CBS (OR 3.75, p<0.0001), and rs202680 FOLH1 (OR 3.00, p<0.0001). Haplotype analyses identified significant associations with BHMT, CBS, FOLH1, MTR, PON2, TCN2 and TYMS haplotypes and stroke risk.
▶Gene variants in the folate‐mediated one‐carbon metabolism (FOCM) pathway as risk factors for conotruncal heart defectsAssociationN=1,236Huiping Zhu et al.(2012)· American Journal of Medical Genetics Part A
This case-control study examined 29 polymorphisms in four folate-mediated one-carbon metabolism pathway genes (MTHFD1, SHMT1, MTHFR, DHFR) in Hispanic and non-Hispanic white populations to assess their association with conotruncal heart defects. MTHFD1 rs11627387 was associated with a 1.7-fold increased risk in both Hispanic mothers (OR=1.7, 95% CI=1.1-2.5) and Hispanic infants (OR=1.7, 95% CI=1.2-2.3). MTHFR rs1801133 (C677T) showed a 2.8-fold increased risk among Hispanic mothers with low dietary folate intake, while rs1801131 (A1298C) showed a 2.0-fold increased risk among those with higher folate intake. Gene-folate interactions were observed, suggesting maternal multivitamin use and dietary folate intake may modify conotruncal heart defect risk.
▶Maternal and infant gene–folate interactions and the risk of neural tube defectsAssociationN=676Analee J. Etheredge et al.(2012)· American Journal of Medical Genetics Part A
Case-control study (222 cases, 454 controls) examining gene-folate interactions in five folate-related genes (MTHFD1, MTHFR, SHMT1, DHFR, TYMS) and neural tube defect risk. Maternal MTHFR SNPs rs1476413, rs1801131, and rs1801133 showed decreased NTD risk with low folate intake (OR=0.55-0.69, 80% CI); infant MTHFD1 SNPs rs2236224, rs2236225, and rs11627387 showed increased risk (OR=1.53-4.25, 80% CI); maternal SHMT1 rs669340 showed protective gene-only effect (OR=0.69, 95% CI: 0.49-0.96).
▶Folate and vitamin B12-related genes and risk for omphaloceleAssociationN=930James L. Mills et al.(2012)· Human Genetics
Case-control study of 169 omphalocele cases and 761 controls examining variants in folate, vitamin B12, and homocysteine metabolism genes. Variants in transcobalamin receptor (TCblR) rs2232775 (Q8R) and methylenetetrahydrofolate reductase (MTHFR) rs1801131 (1298A>C) were significantly associated with omphalocele (TCblR OR=3.20, p=0.0017; MTHFR OR=2.04, p=0.028). Additional race-ethnicity-specific associations were found with TCN2, BHMT rs3733890, and FOLH1 variants, suggesting disruption of methylation reactions as a potential risk factor.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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