|(C;T)||1.25||Possible increased risk of birth defects|
|(T;T)||1.5||Slightly (~1.5x) higher risk for Caucasian mothers to give birth to NTD children|
rs2236225, also known as c.1958G>A, G1958A, p.Arg653Gln and R653Q, is a SNP in the MTHFD1 gene on chromosome 14, involved in folate metabolism.
The Arg653Gln mutation was studied and found not to affect the enzyme activity when present, but did seem to decrease the half-life and stability. [PMID 18767138]
A study in Quebec showed an association in children with mutations in MTHFD1 having increased risk for heart defects, possibly in a folate status dependent manner (IE more so if their mother was not getting enough folate during pregnancy). [PMID 18767138]
A 2014 meta-analysis of nine studies totaling 4,302 cases of children born with neural tube defects concluded that Caucasian mothers carrying rs2236225(C;T) or rs2236225(T;T) alleles were at increased risk, of about 1.5 - 1.7x, of having affected children compared to mothers with no (T) alleles. However, they cautioned that their results should be "viewed with caution" given the statistical uncertainties inherent in these studies. [PMID 24977710][PMID 19130090] rs1076991 C > T exerts a significant effect on promoter activity in vitro and along with rs2236225 G > A influences embryonic development.
|Disease Association||Defects in MTHFD1 may be associated with elevated risk for neural tube defects (NTD) such as spina bifida.|
[PMID 20217437] Association analysis of CbetaS 844ins68 and MTHFD1 G1958A polymorphisms with Alzheimer's disease in Chinese
[PMID 21429654] Polymorphic variants of folate and choline metabolism genes and the risk of endometriosis-associated infertility
|Disease||Neural tube defects|
|CLNDBN||Neural tube defects, folate-sensitive, susceptibility to|
|CLNSRC||OMIM Allelic Variant|
[PMID 16816108] Common genetic polymorphisms affect the human requirement for the nutrient choline.
[PMID 17035141] Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions.
[PMID 17613168] Gene response elements, genetic polymorphisms and epigenetics influence the human dietary requirement for choline.
[PMID 17616785] Lymphocyte gene expression in subjects fed a low-choline diet differs between those who develop organ dysfunction and those who do not.
[PMID 18203168] Folate and one-carbon metabolism gene polymorphisms and their associations with oral facial clefts.
[PMID 18221821] Association of polymorphisms in one-carbon metabolizing genes and lung cancer risk: a case-control study in Chinese population.
[PMID 18661527] Folate-related gene polymorphisms as risk factors for cleft lip and cleft palate.
[PMID 18789905] Genetic polymorphisms in methyl-group metabolism and epigenetics: lessons from humans and mouse models.
[PMID 18992148] Low-penetrance alleles predisposing to sporadic colorectal cancers: a French case-controlled genetic association study.
[PMID 19064578] No association of single nucleotide polymorphisms in one-carbon metabolism genes with prostate cancer risk.
[PMID 19112534] Lack of association of polymorphisms in homocysteine metabolism genes with pseudoexfoliation syndrome and glaucoma.
[PMID 19167960] Genetic variants in phosphatidylethanolamine N-methyltransferase and methylenetetrahydrofolate dehydrogenase influence biomarkers of choline metabolism when folate intake is restricted.
[PMID 19261726] Epigenetic mechanisms for nutrition determinants of later health outcomes.
[PMID 19379518] Development of a fingerprinting panel using medically relevant polymorphisms.
[PMID 19493349] 118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects.
[PMID 19706844] Association of folate-pathway gene polymorphisms with the risk of prostate cancer: a population-based nested case-control study, systematic review, and meta-analysis.
[PMID 19808787] Genetics of human neural tube defects.
[PMID 20018050] Application of sex-specific single-nucleotide polymorphism filters in genome-wide association data.
[PMID 20565774] Population based allele frequencies of disease associated polymorphisms in the Personalized Medicine Research Project.
[PMID 20890936] Maternal polymorphisms in folic acid metabolic genes are associated with nonsyndromic cleft lip and/or palate in the Brazilian population.
[PMID 21349258] Folate and choline metabolism gene variants and development of uterine cervical carcinoma.
[PMID 21688148] Polymorphic variants of genes involved in homocysteine metabolism in celiac disease.
[PMID 22183302] Folate and choline metabolism gene variants in relation to ovarian cancer risk in the Polish population.
|qualified_impact||Insufficiently evaluated pharmacogenetic|
[PMID 24254627] MTHFR rs2274976 polymorphism is a risk marker for nonsyndromic cleft lip with or without cleft palate in the brazilian population
[PMID 22903727] Maternal and infant gene-folate interactions and the risk of neural tube defects.
[PMID 25039261] Association Study of MTHFD1 Coding Polymorphisms R134K and R653Q With Migraine Susceptibility
[PMID 25074646] Associations of Common Variants in Methionine Metabolism Pathway Genes with Plasma Homocysteine and the Risk of Type 2 Diabetes in Han Chinese
[PMID 25921832] Evidence for negative selection of gene variants that increase dependence on dietary choline in a Gambian cohort