NM_002454.2(MTRR):c.66A>G (p.Ile22Met) AND Down syndrome, susceptibility to

Clinical significance:risk factor (Last evaluated: Jul 1, 2005)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_002454.2(MTRR):c.66A>G (p.Ile22Met)]

NM_002454.2(MTRR):c.66A>G (p.Ile22Met)

MTRR:5-methyltetrahydrofolate-homocysteine methyltransferase reductase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_002454.2(MTRR):c.66A>G (p.Ile22Met)
Other names:
  • NC_000005.10:g.7870860A>G
  • NG_008856.1:g.6757A>G
  • NM_002454.2:c.66A>G
  • NM_024010.2:c.147A>G
  • NP_002445.2:p.Ile22Met
  • NP_076915.2:p.Ile49Met
  • NC_000005.9:g.7870973A>G
  • NR_134480.1:n.203A>G
  • Q9UBK8:p.Ile49Met
Protein change:
PharmGKB Clinical Annotation: 981202393; UniProtKB: Q9UBK8#VAR_012836; OMIM: 602568.0003; dbSNP: rs1801394
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_002454.2:c.66A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_134480.1:n.203A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]


Down syndrome, susceptibility to

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000027645OMIMno assertion criteria providedrisk factor
(Jul 1, 2005)
germlineliterature only

PubMed (7)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only



Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria.

Leclerc D, Wilson A, Dumas R, Gafuik C, Song D, Watkins D, Heng HH, Rommens JM, Scherer SW, Rosenblatt DS, Gravel RA.

Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3059-64.

PubMed [citation]

A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida.

Wilson A, Platt R, Wu Q, Leclerc D, Christensen B, Yang H, Gravel RA, Rozen R.

Mol Genet Metab. 1999 Aug;67(4):317-23.

PubMed [citation]
See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000027645.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (7)


The cloning of the cDNA for MTRR (Leclerc et al., 1998) led to the identification of a 66A-G polymorphism, resulting in an ile22-to-met (I22M) substitution, that was shown by Wilson et al. (1999) to be associated with increased risk for the neural tube defect spina bifida (see 601634). Serum deficiency of vitamin B12 increased the effect.

Hobbs et al. (2000) evaluated the frequencies of the MTHFR 677C-T (607093.0003) and MTRR 66A-G polymorphisms in DNA samples from 157 mothers of children with Down syndrome (190685) and 144 control mothers. Odds ratios were calculated for each genotype separately and for potential gene-gene interactions. The results were consistent with the preliminary observations of James et al. (1999) that the MTHFR 677C-T polymorphism is more prevalent among mothers of children with Down syndrome than among control mothers, with an odds ratio (OR) of 1.91 (95% CI, 1.19-3.05). In addition, the homozygous MTRR 66A-G polymorphism was independently associated with a 2.57-fold increase in estimated risk (95% CI, 1.33-4.99). The combined presence of both polymorphisms was associated with a greater risk of Down syndrome than was the presence of either alone, with an OR of 4.08 (95% CI, 1.94-8.56). The 2 polymorphisms appeared to act without a multiplicative interaction. The association between folate deficiency and DNA hypomethylation lent support to the possibility that the increased frequency of the MTHFR and MTTR polymorphisms observed in this study may be associated with chromosomal nondisjunction and Down syndrome.

Doolin et al. (2002) studied the potential involvement of both the maternal and embryonic genotypes in determining risk of spina bifida. Analysis of data on this polymorphism and the A2756G polymorphism of the methionine synthase gene (156570.0008) provided evidence that both variants influence the risk of spina bifida via the maternal rather than the embryonic genotype. For both variants the risk of having a child with spina bifida appeared to increase with the number of high-risk alleles in the maternal genotype.

Bosco et al. (2003) studied the influence of polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677C-T and 1298A-C, 607093.0004), methionine synthase (MTR 2756A-G), and methionine synthase reductase (MTRR 66A-G) on the risk of being a Down syndrome (190685) case or of having a child with Down syndrome (case mother). Plasma homocysteine and other factors were likewise studied. They found that after adjustment for age, total homocysteine and MTR 2756 AG/GG genotype were significant risk factors for having a Down syndrome child, with odds ratio (OR) of 6.7 and 3.5, respectively. The MTR 2756 AG/GG genotype increased significantly the risk of being a Down syndrome case, with an OR of 3.8. Double heterozygosity for MTR 2756 AG/MTRR 66 AG was the single combined genotype that was a significant risk factor for having a Down syndrome child, with an OR estimated at 5.0, after adjustment for total homocysteine level.

O'Leary et al. (2005) found no association between the 66A-G polymorphism and neural tube defects in an Irish population comprising 470 patients and 447 mothers of cases. A dominant paternal effect was observed (OR of 1.46).

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 30, 2019

Support Center