MTHFR A222V - GET-Evidence

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Currentness:

MTHFR A222V

(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 ):
SIFT=tolerated(0.05);
PolyPhen=possibly_damaging(0.235);
Condel=deleterious(0.796)
Mutation Tasting Prediction: Polymorphism, P value: 0.001681; no protein features affected.

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

Impact

Insufficiently evaluated pharmacogenetic

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

Inheritance pattern

unknown

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)

Publications
 

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PubMed PMID: 11418485

 

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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.

 

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PubMed PMID: 15643524

 

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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.

 

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PubMed PMID: 17976958

 

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.

 

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PubMed PMID: 18580170

 

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PubMed PMID: 19005482

 

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PubMed PMID: 19016697

 

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PubMed PMID: 19303062

 

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PubMed PMID: 19581920

 

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PubMed PMID: 21044746

 

Genomes
 

hu011C57 - CGI sample GS01669-DNA_B05 from PGP sample 86486261
het A @ chr1:11856378

 

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

 

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

 

hu232307 - PGP14 (hu232307) build 36, substitution variants, hu232307 build 36 substitution variants
het A @ chr1:11778965

 

hu2D6140 - CGI sample GS01173-DNA_F06 from PGP sample 64191565
het A @ chr1:11856378

 

hu3215A7 - PGP12 (hu3215A7) build 36, substitution variants, hu3215A7 build 36 substitution variants
hom A @ chr1:11778965

 

hu34D5B9 - CGI sample GS01173-DNA_C07 from PGP sample 92161424, hu34D5B9 exome
het A @ chr1:11856378

 

hu38168C - CGI sample GS01173-DNA_H06 from PGP sample 91708424
het A @ chr1:11856378

 

hu3CAB43 - CGI sample GS01175-DNA_D03 from PGP sample 27486199
het A @ chr1:11856378

 

hu4040B8 - CGI sample GS01175-DNA_D01 from PGP sample 31286272
het A @ chr1:11856378

 

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

 

hu44DCFF - CGI sample GS01669-DNA_C07 from PGP sample 74521372
hom A @ chr1:11856378

 

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

 

hu6E4515 - PGP15 (hu6E4515) build 37, from CGI var (software ver 1.12.0.47), CGI sample GS000005532
hom A @ chr1:11856378

 

hu728FFF - PGP11 (hu728FFF) build 36, substitution variants, hu728FFF build 36 substitution variants
het A @ chr1:11778965

 

hu72A81D - CGI sample GS01173-DNA_C02 from PGP sample 10366372
het A @ chr1:11856378

 

hu7A4AD1 - CGI sample GS01669-DNA_C05 from PGP sample 42408046
het A @ chr1:11856378

 

hu92C40A - CGI sample GS01175-DNA_G03 from PGP sample 92527586
het A @ chr1:11856378

 

hu92FD55 - CGI sample GS01669-DNA_A04 from PGP sample 08188426
het A @ chr1:11856378

 

huAE4A11 - CGI sample GS01669-DNA_F02 from PGP sample 40767107
het A @ chr1:11856378

 

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

 

huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
het A @ chr1:11856378

 

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

 

huD37D14 - CGI sample GS01175-DNA_A04 from PGP sample 13272228
hom A @ chr1:11856378

 

huD81F3D - CGI sample GS01173-DNA_D06 from PGP sample 69488604
het A @ chr1:11856378

 

huFAF983 - CGI sample GS01175-DNA_F02 from PGP sample 95788191
het A @ chr1:11856378

 

huFFAD87 - CGI sample GS01669-DNA_H05 from PGP sample 10971581
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
 

    dbSNP
  • rs1801133
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GWAS
  • 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
    www.ncbi.nlm.nih.gov/pubmed/20031578
    PharmGKB
  • [fluorouracil; folic acid; methotrexate]
    Well studied, associated with multiple phenotypes.
    www.pharmgkb.org/search/annotatedGene/mthfr/
  • [Drug Toxicity; Thrombocytopenia]
    [methotrexate]
    This variant is associated with methotrexated-induced mucositis, thrombocytopenia and hepatic toxicity
    www.ncbi.nlm.nih.gov/pubmed/17488658
  • [Alopecia; Arthritis, Rheumatoid; Drug Toxicity]
    [methotrexate]
    This variant is associated with methotrexated-induced alopecia in African Americans with rheumatoid arthritis.
    www.ncbi.nlm.nih.gov/pubmed/18381794
  • [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.
    www.ncbi.nlm.nih.gov/pubmed/19581920
  • [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.
    www.ncbi.nlm.nih.gov/pubmed/19303062
  • [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.
    www.ncbi.nlm.nih.gov/pubmed/15643524
  • [Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma]
    [methotrexate]
    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.
    www.ncbi.nlm.nih.gov/pubmed/12915598
  • [Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Transplantation]
    [methotrexate]
    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.
    www.ncbi.nlm.nih.gov/pubmed/11418485
  • [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.
    www.ncbi.nlm.nih.gov/pubmed/17976958
  • [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.
    www.ncbi.nlm.nih.gov/pubmed/17976958
  • [Arthritis, Rheumatoid]
    [methotrexate]
    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.
    www.ncbi.nlm.nih.gov/pubmed/11710708
  • [Leukemia; Leukemia, Promyelocytic, Acute; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma]
    [methotrexate]
    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.
    www.ncbi.nlm.nih.gov/pubmed/12453860
  • [Arthritis, Rheumatoid]
    [methotrexate]
    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.
    www.ncbi.nlm.nih.gov/pubmed/11710708
  • [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
    www.ncbi.nlm.nih.gov/pubmed/19005482
  • [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.
    www.ncbi.nlm.nih.gov/pubmed/16572443
  • [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.
    www.ncbi.nlm.nih.gov/pubmed/19016697
  • [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.
    www.ncbi.nlm.nih.gov/pubmed/18580170
    PolyPhen-2
  • 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 ...
    www.ncbi.nlm.nih.gov/pmc/articles/PMC1913583
  • MTHFR - SNPedia
    The MTHFR gene encodes the vitamin-dependent enzyme, methylenetetrahydrofolate reductase. ... rs1801133, also known as A222V. rs1801131, also known as E429A ...
    www.snpedia.com/index.php?title=MTHFR
  • The methylenetetrahydrofolate reductase (MTHFR) variant c ...
    The methylenetetrahydrofolate reductase (MTHFR) variant c.677C>T (A222V) influences overall survival of patients with glioblastoma multiforme ...
    neuro-oncology.oxfordjournals.org/cgi/content/abstract/...
  • 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 ...
    ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A52348
  • 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 ...
    scribd.com/doc/3222775/The-prevalence-of-folateremedial-MTHFR...
  • GENETIC/NUTRIENT DETERMINANTS OF CONGENITAL HEART DEFECTS IN ...
    Although the allele frequency was low for MTHFR A222V, this variant was also increased in cases (p=.04) alone. Conclusion: Previously implicated ...
    www.ashg.org/genetics/ashg07s/f11214.htm
  • 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) ...
    plosone.org/article/info:doi/10.1371/journal.pone.0006540
  • 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 ...
    www.thieme.de/abstracts/aktneu/abstracts2003/daten/p431.html
  • 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 ...
    biochem.arizona.edu/classes/.../Lecture16/yeastMTHFR.pdf
  • 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 ...
    www.pharmgkb.org/do/serve?objId=PA26551&objCls=Gene

Other in silico analyses
 

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

Edit history
 

Gene search

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