MTHFR A222V - GET-Evidence

Note: This variant has not been sufficiently evaluated by a GET-Evidence editor.

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(MTHFR Ala222Val)

Short summary

this is a.k.a. C677T and Rs1801133. Modulates toxicity of methotrexate in patients.

Variant evidence
Computational 3

PolyPhen: Probably damaging0.970
SIFT: Affect protein function 0.00
GVGD: GV 0.00; GD 65.28; Class C65
Variant Effect Predictor (Ensembl ):
Mutation Tasting Prediction: Polymorphism, P value: 0.001681; no protein features affected.

Functional -
Case/Control -
Familial -
Clinical importance
Severity -
Treatability -
Penetrance -


Insufficiently evaluated pharmacogenetic

(The "insufficiently evaluated" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary


Allele frequency

  • A @ chr1:11856378: 27.2% (2925/10758) in EVS
  • A @ chr1:11778964: 20.3% (26/128) in GET-Evidence
  • Frequency shown in summary reports: 27.2% (2925/10758)


Ulrich CM, Yasui Y, Storb R, Schubert MM, Wagner JL, Bigler J, Ariail KS, Keener CL, Li S, Liu H, Farin FM, Potter JD. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood. 2001 Jul 1;98(1):231-4. PubMed PMID: 11418485.


van Ede AE, Laan RF, Blom HJ, Huizinga TW, Haagsma CJ, Giesendorf BA, de Boo TM, van de Putte LB. The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients. Arthritis Rheum. 2001 Nov;44(11):2525-30. PubMed PMID: 11710708.


Chiusolo P, Reddiconto G, Casorelli I, Laurenti L, Sorà F, Mele L, Annino L, Leone G, Sica S. Preponderance of methylenetetrahydrofolate reductase C677T homozygosity among leukemia patients intolerant to methotrexate. Ann Oncol. 2002 Dec;13(12):1915-8. PubMed PMID: 12453860.


Kishi S, Griener J, Cheng C, Das S, Cook EH, Pei D, Hudson M, Rubnitz J, Sandlund JT, Pui CH, Relling MV. Homocysteine, pharmacogenetics, and neurotoxicity in children with leukemia. J Clin Oncol. 2003 Aug 15;21(16):3084-91. PubMed PMID: 12915598.


Shen H, Newmann AS, Hu Z, Zhang Z, Xu Y, Wang L, Hu X, Guo J, Wang X, Wei Q. Methylenetetrahydrofolate reductase polymorphisms/haplotypes and risk of gastric cancer: a case-control analysis in China. Oncol Rep. 2005 Feb;13(2):355-60. PubMed PMID: 15643524.


Wessels JA, de Vries-Bouwstra JK, Heijmans BT, Slagboom PE, Goekoop-Ruiterman YP, Allaart CF, Kerstens PJ, van Zeben D, Breedveld FC, Dijkmans BA, Huizinga TW, Guchelaar HJ. Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes. Arthritis Rheum. 2006 Apr;54(4):1087-95. PubMed PMID: 16572443.


Gemmati D, Ongaro A, Tognazzo S, Catozzi L, Federici F, Mauro E, Della Porta M, Campioni D, Bardi A, Gilli G, Pellati A, Caruso A, Scapoli GL, De Mattei M. Methylenetetrahydrofolate reductase C677T and A1298C gene variants in adult non-Hodgkin's lymphoma patients: association with toxicity and survival. Haematologica. 2007 Apr;92(4):478-85. PubMed PMID: 17488658.


Ellingrod VL, Miller DD, Taylor SF, Moline J, Holman T, Kerr J. Metabolic syndrome and insulin resistance in schizophrenia patients receiving antipsychotics genotyped for the methylenetetrahydrofolate reductase (MTHFR) 677C/T and 1298A/C variants. Schizophr Res. 2008 Jan;98(1-3):47-54. Epub 2007 Oct 31. PubMed PMID: 17976958; PubMed Central PMCID: PMC2271139.


Boccia S, Hung R, Ricciardi G, Gianfagna F, Ebert MP, Fang JY, Gao CM, Götze T, Graziano F, Lacasaña-Navarro M, Lin D, López-Carrillo L, Qiao YL, Shen H, Stolzenberg-Solomon R, Takezaki T, Weng YR, Zhang FF, van Duijn CM, Boffetta P, Taioli E. Meta- and pooled analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer risk: a huge-GSEC review. Am J Epidemiol. 2008 Mar 1;167(5):505-16. Epub 2007 Dec 27. PubMed PMID: 18162478.


Ranganathan P, Culverhouse R, Marsh S, Mody A, Scott-Horton TJ, Brasington R, Joseph A, Reddy V, Eisen S, McLeod HL. Methotrexate (MTX) pathway gene polymorphisms and their effects on MTX toxicity in Caucasian and African American patients with rheumatoid arthritis. J Rheumatol. 2008 Apr;35(4):572-9. Epub 2008 Mar 15. PubMed PMID: 18381794.


Nagele P, Zeugswetter B, Wiener C, Burger H, Hüpfl M, Mittlböck M, Födinger M. Influence of methylenetetrahydrofolate reductase gene polymorphisms on homocysteine concentrations after nitrous oxide anesthesia. Anesthesiology. 2008 Jul;109(1):36-43. PubMed PMID: 18580170.


Rocha V, Porcher R, Fernandes JF, Filion A, Bittencourt H, Silva W Jr, Vilela G, Zanette DL, Ferry C, Larghero J, Devergie A, Ribaud P, Skvortsova Y, Tamouza R, Gluckman E, Socie G, Zago MA. Association of drug metabolism gene polymorphisms with toxicities, graft-versus-host disease and survival after HLA-identical sibling hematopoietic stem cell transplantation for patients with leukemia. Leukemia. 2009 Mar;23(3):545-56. Epub 2008 Nov 13. PubMed PMID: 19005482.


Warren RB, Smith RL, Campalani E, Eyre S, Smith CH, Barker JN, Worthington J, Griffiths CE. Outcomes of methotrexate therapy for psoriasis and relationship to genetic polymorphisms. Br J Dermatol. 2009 Feb;160(2):438-41. Epub 2008 Oct 25. PubMed PMID: 19016697; PubMed Central PMCID: PMC2680291.


Tanaka T, Scheet P, Giusti B, Bandinelli S, Piras MG, Usala G, Lai S, Mulas A, Corsi AM, Vestrini A, Sofi F, Gori AM, Abbate R, Guralnik J, Singleton A, Abecasis GR, Schlessinger D, Uda M, Ferrucci L. Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations. Am J Hum Genet. 2009 Apr;84(4):477-82. Epub 2009 Mar 19. Erratum in: Am J Hum Genet. 2009 May;84(5):712. PubMed PMID: 19303062; PubMed Central PMCID: PMC2667971.


Carr DF, Whiteley G, Alfirevic A, Pirmohamed M; FolATED study team. Investigation of inter-individual variability of the one-carbon folate pathway: a bioinformatic and genetic review. Pharmacogenomics J. 2009 Oct;9(5):291-305. Epub 2009 Jul 7. Review. PubMed PMID: 19581920.


Castillo-Fernández O, Santibáñez M, Bauza A, Calderillo G, Castro C, Herrera R, Serrano A, Arrieta O, Herrera LA. Methylenetetrahydrofolate reductase polymorphism (677 C>T) predicts long time to progression in metastatic colon cancer treated with 5-fluorouracil and folinic acid. Arch Med Res. 2010 Aug;41(6):430-5. PubMed PMID: 21044746.




hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het A @ chr1:11856378


hu04FD18 - CGI sample GS00253-DNA_F01_200_37
het A @ chr1:11856378









hu43860C - CGI sample GS00253-DNA_A01_200_37
het A @ chr1:11856378



hu604D39 - CGI sample GS00253-DNA_B02_200_37
het A @ chr1:11856378









huAE6220 - CGI sample GS00253-DNA_H01_200_37
het A @ chr1:11856378



huBEDA0B - CGI sample GS00253-DNA_C01_200_37
het A @ chr1:11856378






GS07357 - var-GS07357-1100-36-ASM
het A @ chr1:11778965


GS10851 - var-GS10851-1100-36-ASM
het A @ chr1:11778965


GS18505 - var-GS18505-1100-36-ASM
het A @ chr1:11778965


GS18508 - var-GS18508-1100-36-ASM
het A @ chr1:11778965


GS18555 - var-GS18555-1100-36-ASM
het A @ chr1:11778965


GS18558 - var-GS18558-1100-36-ASM
het A @ chr1:11778965


GS18940 - var-GS18940-1100-36-ASM
het A @ chr1:11778965


GS18956 - var-GS18956-1100-36-ASM
het A @ chr1:11778965


GS19648 - var-GS19648-1100-36-ASM
het A @ chr1:11778965


GS19670 - var-GS19670-1100-36-ASM
het A @ chr1:11778965


GS19701 - var-GS19701-1100-36-ASM
het A @ chr1:11778965


GS19735 - var-GS19735-1100-36-ASM
het A @ chr1:11778965


GS20502 - var-GS20502-1100-36-ASM
het A @ chr1:11778965


GS20509 - var-GS20509-1100-36-ASM
het A @ chr1:11778965


Other external references

  • rs1801133
  • Plasma homocysteine (rs1801133-A)
    Pare 1-Apr-09 in Circ Cardiovasc Genet
    OR or beta: 0.05 [NR] unit increase in log(homocy
    Risk allele frequency: 0.33
    p-value: 8.00E-35 (WGHS)
    Initial sample: 13,974 white females
    Replication sample: 840 European ancestry females
  • [fluorouracil; folic acid; methotrexate]
    Well studied, associated with multiple phenotypes.
  • [Drug Toxicity; Thrombocytopenia]
    This variant is associated with methotrexated-induced mucositis, thrombocytopenia and hepatic toxicity
  • [Alopecia; Arthritis, Rheumatoid; Drug Toxicity]
    This variant is associated with methotrexated-induced alopecia in African Americans with rheumatoid arthritis.
  • [Breast Neoplasms; Colorectal Neoplasms; Heart Diseases; Psychophysiologic Disorders]
    This variant protein has reduced catalytic activity and thermolability, and is thus associated with elevated homocysteine levels under conditions of impaired folate status.
  • [Coronary Disease; Neurologic Manifestations; Stroke]
    The T allele of this SNP was found to be associated with higher blood concentration of homocysteine in Italians (Combined studies of Tuscan Italians ( inCHIANTI:N =1175 and Progetto Nutrizione study:N = 687) and Sardinians (SardiNIA: N=1115)) but not in the BLSA cohort (from Baltimore-Washington DC). The study authors inferred that this was related to U.S. food fortification and hence higher folate status.
  • [Stomach Neoplasms]
    In a case control study of Asian gastric cancer (n=633), individuals with 6 variant alleles of three MTHFR common variants (i.e. C677T, A1298C and G1793A) were at increased risk for gastric cardia adenocarcinoma (OR =4.64, 95% CI =1.34-16.01) compared with those having 0-2 variants.
  • [Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma]
    In 53 newly diagnosed patients with childhood acute lymphoblastic leukemia who were treated with two courses of high-dose methotrexate (MTX), no association was found between MTX-induced increases in plasma or cerebrospinal fluid homocysteine levels or MTX-induced toxicity (seizures or thrombosis) based upon the MTHFR 677C>T or RFC (SLC19A1) 80G>A genotypes.
  • [Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Transplantation]
    In patients with chronic myelogenous leukemia undergoing bone marrow transplantation and taking methotrexate, carriers of the MTHFR 677TT genotype versus CT and CC genotypes showed significantly greater post-allograft drug-induced toxicity in the form of oral mucositis (p=0.046), and a non-significant trend toward slower platelet recovery.
  • [Insulin Resistance; metabolic syndrome]
    Risk or phenotype-associated allele: T. Phenotype: 53% of T allele carriers met metabolic syndrome criteria, compared with 23% in the CC genotype group. Study size: 58. Study population/ethnicity: Individuals with schizophrenia receiving atypical antipsychotics (AAPs) for 12 or more months. Over 85% of the subjects were Caucasian. Significance metric(s): OR = 3.7; p = 0.02. Type of association: CO.
  • [Insulin Resistance; metabolic syndrome]
    Risk or phenotype-associated allele: T. Phenotype: Both waist circumference and the MTHFR genotype were significant factors associated with insulin resistance. Study size: 58. Study population/ethnicity: Individuals with schizophrenia receiving atypical antipsychotics (AAPs) for 12 or more months. Over 85% of the subjects were Caucasian. Significance metric(s): p < 0.0001. Type of association: CO.
  • [Arthritis, Rheumatoid]
    MTHFR rs1801133, 667CT or 667TT genotypes were associated with an increased risk of methotrexate treatment discontinuation due to adverse events (relative risk 2.01), mostly as a result of increased risk of elevated levels of liver enzyme alanine aminotransferase (relative risk 2.38) in rheumatoid arthritis patients.
  • [Leukemia; Leukemia, Promyelocytic, Acute; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma]
    In a retrospective analysis of 61 Italian patients experiencing methotrexate toxicity during treatment for acute lymphoblastic leukemia or acute promyelocytic leukemia, carriers of the MTHFR 677TT genotype (60%) showed significantly greater drug-induced toxicity (p=0.03) compared to CC and CT genotypes.
  • [Arthritis, Rheumatoid]
    Risk or phenotype-associated allele: CT and TT genotypes. Phenotype: The 677 CT or TT genotypes were associated with greater incidence of discontinuation of methorexate treatment because of adverse events, mainly due to elevation of liver enzymes. Study size: 236. Study population/ethnicity: Patients who started methorexate treatment with (n = 157) or without (n = 79) folic or folinic acid supplementation for rheumatoid arthritis. Significance metric(s): RR = 2.01 Type of association: CO, GN.
  • [Graft vs Host Disease]
    Risk or phenotype-associated allele: T. Phenotype: MTHFR:677T genotype in the transplant recipient was associated with acute graft vs host disease. Study size:107 . Study population/ethnicity: Donors and patients with leukemia after HLA-identical hematopoietic stem cell transplantation, France. Significance metric(s): p = 0.03. Type of association: CO
  • [Arthritis, Rheumatoid]
    [folic acid; methotrexate]
    Given methotrexate and folic acid therapy, patients with the MTHFR 1298AA / 677CC diplotype showed greater clinical improvement for early rheumatoid arthritis.
  • [Psoriasis]
    [folic acid; methotrexate]
    In 330 patients who completed 3 months methotrexate treatment for psoriasis, no significant genotypic associations were found between clinical outcome (e.g. efficacy, toxicity) and 50 SNPs in pathway genes for methotrexate metabolism (ATIC, FPGS, GGH, MTHFR), including 47 common ( >5% minor allele frequency) haplotype-tagging SNPs (r(2) > 0.8) plus 3 additional SNPs.
  • [nitrous oxide]
    Risk or phenotype-associated allele(s): T/T. Phenotype:Patients with a homozygous MTHFR 677C>T mutation (n = 25) developed higher plasma homocysteine concentrations (median [interquartile range], 14.9 [10.0-26.4] microm) than wild-type or heterozygous patients (9.3 [7.5-15.5] microm; n = 115). The change in homocysteine after nitrous oxide anesthesia was tripled in homozygous patients compared with wild-type (5.6 microm [+60%] vs. 1.8 microm [+22%]). Study size: 140. Study population/ethnicity: healthy patients undergoing elective surgery. Type of association: GN.
  • Score: 0.858 (probably damaging)
    Web search results (594 hits -- see all)
  • Metabolism of Low-Dose Inorganic Arsenic in a Central ...
    The mean and confidence interval of the %MA by genotype of MTHFR A222V, MTHFR E429A, GSTO1 A140D, and AS3MT M287T for (A) males and (B) females. Multivariate analyses ...
  • MTHFR - SNPedia
    The MTHFR gene encodes the vitamin-dependent enzyme, methylenetetrahydrofolate reductase. ... rs1801133, also known as A222V. rs1801131, also known as E429A ...
  • The methylenetetrahydrofolate reductase (MTHFR) variant c ...
    The methylenetetrahydrofolate reductase (MTHFR) variant c.677C>T (A222V) influences overall survival of patients with glioblastoma multiforme ...
  • Molecular Biology of Methylenetetrahydrofolate Reductase ...
    The cloning of the MTHFR coding sequence was initially followed by the ... The A222V polymorphism in human MTHFR has been mimicked in the E. coli enzyme by ...
  • The prevalence of folate-remedial MTHFR enzyme variants in humans
    The prevalence of folate-remedial MTHFR enzyme variants in humans. ... Indeed, A222V is a risk factor for colon cancer when dietary folate intakes are low but may actually be ...
    Although the allele frequency was low for MTHFR A222V, this variant was also increased in cases (p=.04) alone. Conclusion: Previously implicated ...
  • PLoS ONE: Lack of Association between Genetic Polymorphisms ...
    PLoS ONE: an inclusive, peer-reviewed, open-access resource from the PUBLIC LIBRARY OF SCIENCE. ... of the MTHFR gene results in the substitution of valine for alanine (p.A222V) ...
  • P431 : The thermolabile MTHFR variant c.677C>T (A222V ...
    The thermolabile MTHFR variant c.677C>T (A222V) contributes to phenotypic variability in ... The MTHFR c.677C>T (A622V) variant was significantly more frequent in ...
  • Functional Characterization of Human ...
    Expression of the human MTHFR cDNA in a yeast strain. deleted for MET11 can restore the strain's MTHFR activ ... MTHFR, C677T (A222V) and A1298C (E428A), have also been ...
  • CLCN6 [PharmGKB]
    MTHFR: c.677C>T; 677C>T; p.A222V; A222V. Related Diseases: Breast ... rs1801133 at chr1:11778965 in CLCN6, MTHFR. MTHFR rs1801133, 667CT or 667TT genotypes were ...

Other in silico analyses

  • NBLOSUM100 score = 2
  • GET-Evidence autoscore = 4

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