MTRR I49M - GET-Evidence



(MTRR Ile49Met)

Short summary

This common variant (HapMap allele frequency of 31.3%) in a protein involved in folate (B9) and cobalamin (B12) metabolism and is often reported as “MTRR I22M” (an alternative transcript position). Mothers homozygous for this variant are associated with having around a increased chance of a child with Down syndrome (risk of 0.4%, average risk in population is 0.25%). Notably, age plays a far larger role in the rate of Down syndrome (risk is 4.5% for a mother 45-years-of-age), and it is unknown how this variant may combine with the effect of age. There are conflicting reports associating this variant with incidence of neural tube defects, possibly when combined with MTHFR A222V.

Variant evidence
Computational 3

Polyphen 2 predicts “possibly damaging” effect.
PolyPhen: Probably damaging 0.520
SIFT: Affect protein function 0.00
GVGD: GV 0.00; GD 10.12; Class C0
Variant Effect Predictor (Ensembl ):
Mutation Tasting Prediction: Polymorphism, P value: 0.136340; protein features (might be) affected (aa 32-174 Flavodoxin-like gets lost).

Functional -
Case/Control 3

p = 0.014

See Hobbs CA et al. 2000 (10930360).

Clinical importance
Severity 4

Down’s syndrome causes serious disability.

Treatability 2

Vitamin supplementation during pregnancy may help to compensate for the variant.

Penetrance 1

~.15% attributable increased risk

See Hobbs CA et al. 2000 (10930360), unpublished research (below).



Low clinical importance, Likely pathogenic

(The "low clinical importance, likely" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary

Assuming a 1/800 risk of Down’s syndrome per child, a woman with an average of 2 children would have a lifetime risk of ~1/400 or 0.25%. Based on this, the data from Hobbs et al. suggests being homozygous has attributable increased risk of 0.15% above average risk using our in house PGP calculator.

Allele frequency

  • G @ chr5:7870973: 45.1% (4854/10758) in EVS
  • G @ chr5:7923972: 38.3% (49/128) in GET-Evidence
  • Frequency shown in summary reports: 45.1% (4854/10758)


Wilson A, Platt R, Wu Q, Leclerc D, Christensen B, Yang H, Gravel RA, Rozen R. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Mol Genet Metab. 1999 Aug;67(4):317-23. PubMed PMID: 10444342.

Studying incidence of neural tube defects (eg spina bifida) found that women with low B12 levels and homozygous for this variant have an increased chance of having children with neural tube defects (OR = 4.8). The do not report p-value for this OR, just a 95% confidence interval (1.5-15.8) and no case numbers.

Hobbs CA, Sherman SL, Yi P, Hopkins SE, Torfs CP, Hine RJ, Pogribna M, Rozen R, James SJ. Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. Am J Hum Genet. 2000 Sep;67(3):623-30. Epub 2000 Aug 7. PubMed PMID: 10930360; PubMed Central PMCID: PMC1287522.

In a study looking at folate metabolism gene polymorphisms and association with Down syndrome, they found MTHFR A222V and MTRR I22M independently associated with mothers of children with Down syndrome. The homozygous MTRR 66A—>G polymorphism (which causes I22M amino acid change) was associated with a 2.57-fold increase in estimated risk (95% CI 1.33-4.99). case+ (GG): 55, case-: (AA/AG): 90, control+: 32, control-: 103. 2-tailed Fisher’s exact: 0.014.

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PubMed PMID: 11807890

From the paper, “The prevalence of the GG homozygous variant genotype alone was significantly higher in cases compared to controls (OR 15.0 [1.94-116], P = 0.0005). In addition, the prevalence of the AG heterozygous genotype alone was significant in cases compared to controls (OR 7.97 [1.04-61.2]; P = 0.017).” They only have one case of AA homozygous in the case group though, so the odds ratio is very imprecise. They report that the variant does not have an effect on plasma homocysteine, ruling this hypothesis out as how the variant has an effect.

Doolin MT, Barbaux S, McDonnell M, Hoess K, Whitehead AS, Mitchell LE. Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida. Am J Hum Genet. 2002 Nov;71(5):1222-6. Epub 2002 Oct 9. PubMed PMID: 12375236; PubMed Central PMCID: PMC385102.

The authors report that the risk of having a child with spina bifida is related to mother rather than child genotype and appears to be increase with the number of copies of this variant, one copy has an OR of 2.05 (95% CI 1.05–3.99) and two copies an OR of 3.15 (95% CI 0.92–10.85).

Relton CL, Wilding CS, Pearce MS, Laffling AJ, Jonas PA, Lynch SA, Tawn EJ, Burn J. Gene-gene interaction in folate-related genes and risk of neural tube defects in a UK population. J Med Genet. 2004 Apr;41(4):256-60. PubMed PMID: 15060097; PubMed Central PMCID: PMC1735724.

In contrast to Wilson et al, they find a protective association for the presence of this variant in cases (p = 0.04) and mothers (p = 0.08). They mention a variety of others studies including Wilson et al, some of which implicate G as pathogenic, some which find no association.

They do find an association of this variant with neural tube defects when combined when this variant is combined with MTHFR 677C>T (A222V, p = 0.003) in the mother, and a maternal MTRR + fetal MTHFR variant (p = 0.001).

O'Leary VB, Mills JL, Pangilinan F, Kirke PN, Cox C, Conley M, Weiler A, Peng K, Shane B, Scott JM, Parle-McDermott A, Molloy AM, Brody LC; Members of the Birth Defects Research Group. Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association. Mol Genet Metab. 2005 Jul;85(3):220-7. Epub 2005 Mar 17. PubMed PMID: 15979034.

In a study of 470 Irish cases of neural tube defect, 447 mothers, and 476 controls, no significant correlation was found for maternal or child I22M genotype. In 423 fathers, however, a dominant effect (carrier of one or two copies) is reported (OR=1.46 [1.10-1.93])

van der Linden IJ, den Heijer M, Afman LA, Gellekink H, Vermeulen SH, Kluijtmans LA, Blom HJ. The methionine synthase reductase 66A>G polymorphism is a maternal risk factor for spina bifida. J Mol Med. 2006 Dec;84(12):1047-54. Epub 2006 Oct 6. PubMed PMID: 17024475.





hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het G @ chr5:7870973


hu04FD18 - CGI sample GS00253-DNA_F01_200_37
hom G @ chr5:7870973


hu0D879F - CGI sample GS00253-DNA_G01_200_37
het G @ chr5:7870973









hu43860C - CGI sample GS00253-DNA_A01_200_37
het G @ chr5:7870973



hu604D39 - CGI sample GS00253-DNA_B02_200_37
hom G @ chr5:7870973








hu9385BA - CGI sample GS00253-DNA_E01_200_37
het G @ chr5:7870973


huAE6220 - CGI sample GS00253-DNA_H01_200_37
hom G @ chr5:7870973




huBEDA0B - CGI sample GS00253-DNA_C01_200_37
hom G @ chr5:7870973




huE80E3D - CGI sample GS00253-DNA_D01_200_37
het G @ chr5:7870973




GS06985 - var-GS06985-1100-36-ASM
het G @ chr5:7923973


GS06994 - var-GS06994-1100-36-ASM
hom G @ chr5:7923973


GS07357 - var-GS07357-1100-36-ASM
het G @ chr5:7923973


GS12004 - var-GS12004-1100-36-ASM
het G @ chr5:7923973


GS18505 - var-GS18505-1100-36-ASM
het G @ chr5:7923973


GS18508 - var-GS18508-1100-36-ASM
het G @ chr5:7923973


GS18526 - var-GS18526-1100-36-ASM
het G @ chr5:7923973


GS18537 - var-GS18537-1100-36-ASM
het G @ chr5:7923973


GS18558 - var-GS18558-1100-36-ASM
het G @ chr5:7923973


GS19017 - var-GS19017-1100-36-ASM
hom G @ chr5:7923973


GS19025 - var-GS19025-1100-36-ASM
het G @ chr5:7923973


GS19129 - var-GS19129-1100-36-ASM
het G @ chr5:7923973


GS19238 - var-GS19238-1100-36-ASM
het G @ chr5:7923973


GS19239 - var-GS19239-1100-36-ASM
hom G @ chr5:7923973


GS19240 - var-GS19240-1100-36-ASM
het G @ chr5:7923973


GS19648 - var-GS19648-1100-36-ASM
het G @ chr5:7923973


GS19703 - var-GS19703-1100-36-ASM
het G @ chr5:7923973


GS19704 - var-GS19704-1100-36-ASM
het G @ chr5:7923973


GS19834 - var-GS19834-1100-36-ASM
hom G @ chr5:7923973


GS20502 - var-GS20502-1100-36-ASM
het G @ chr5:7923973


Other external references

  • rs1801394
  • [Neural Tube Defects; Spina Bifida Cystica]
    Risk or phenotype-associated allele: G Phenotype: Maternal MTRR 66GG genotype was associated with an overall increase in Spina bifida risk. Study size: 413 Study population/ethnicity: Mothers with a child affected by Spina Bifida and control women; Netherlands Significance metric(s): OR= 2.1 (95% CI 1.3-3.3) Type of association: CO

Other in silico analyses

  • NBLOSUM100 score = –1
  • GET-Evidence autoscore = 4

Edit history

Gene search

"GENE" or "GENE A123C":

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