rs162036

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This is a variant in the MTRR gene that changes a lysine to an arginine.

Key Literature Trait Associations

Spina bifida

A population-based case-control study (Shaw et al., 2009) found that the MTRR rs162036 G allele was associated with a roughly 3-fold increased risk of spina bifida (OR=3.0, 95% CI 1.5–5.9) among 259 cases and 359 controls in California. In contrast, O'Leary et al. (2005) found no significant association between K350R and neural tube defects in an Irish population (n=447 mothers, 470 cases, 476 controls). The conflicting results may reflect population-specific folate intake, ancestry differences in allele frequency, or chance findings in small studies. Evidence is insufficient to draw firm conclusions and no large meta-analysis has been conducted specifically on rs162036.

Shaw GM et al. “118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects.” Bmc Medical Genetics (2009)

Allele G

OR 3.00

p —

N 618

Preliminary work

California (multi-ancestry)

O'Leary VB et al. “Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association.” Molecular Genetics and Metabolism (2005)

Allele G

OR —

p —

N 1,393

Preliminary work

Irish

Methionine Synthase Reductase Activity

The MTRR K350A variant (rs162036) is a missense polymorphism (Lys350Ala) in methionine synthase reductase. The G allele changes a lysine to alanine residue, which may affect enzyme function. Some studies have found modest associations with altered homocysteine metabolism, but evidence is inconsistent and the variant has not been independently validated in large meta-analyses.

Laraqui A et al. “Influence of methionine synthase (A2756G) and methionine synthase reductase (A66G) polymorphisms on plasma homocysteine levels and relation to risk of coronary artery disease.” Acta Cardiologica 61(1):51-61 (2006)

Allele G

OR —

p 5.0e-2

Candidate gene study

Du B et al. “Genetic polymorphisms of key enzymes in folate metabolism affect the efficacy of folate therapy in patients with hyperhomocysteinaemia.” The British Journal of Nutrition (2018)

Allele G

OR —

p 5.0e-2

Candidate gene study

Chinese (hyperhomocysteinemia patients)

Li D et al. “Association of genetic and epigenetic variants in one-carbon metabolism gene with folate treatment response in hyperhomocysteinaemia.” European Journal of Clinical Nutrition (2020)

Allele G

OR —

p 4.8e-2

N 230

Candidate gene study

Chinese (hyperhomocysteinemia patients)

Nonobstructive azoospermia

Two small candidate-gene studies in northeast Chinese Han populations examined rs162036 and nonobstructive azoospermia (NOA) risk with contradictory results. Liu et al. (2019) found OR=3.686 (95% CI 1.228–11.066, p<0.05) in 34 NOA patients versus 40 controls, suggesting the G allele may impair MTRR-dependent folate/methionine metabolism critical for spermatogenesis. However, Yang et al. (2018) found no significant association in a larger validation cohort (121 NOA patients, 256 controls). Given the small sample sizes and conflicting results, evidence for this association remains preliminary.

Liu X et al. “Targeted Next-Generation Sequencing Identifies Novel Sequence Variations of Genes Associated with Nonobstructive Azoospermia in the Han Population of Northeast China.” Medical Science Monitor : International Medical Journal of Experimental and Clinical Research (2019)

Allele G

OR 3.69

p 5.0e-2

N 74

Candidate gene study

Han Chinese

Yang X et al. “Association Study Between MTRR, TAF4B, PIWIL1 Variants and Non-Obstructive Azoospermia in Northeast Chinese Han Population.” Clinical Laboratory (2018)

Allele G

OR —

p —

N 377

Candidate gene study

Han Chinese

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ClinVar annotation

Uncertain Significance★★★☆

10 submitters3 publications

Disorders of Intracellular Cobalamin Metabolism; Gastrointestinal stromal tumor; Methylcobalamin deficiency type cblE (HMAE); not specified

View on ClinVar →

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Research that mentions this SNP (2)

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Association of main folate metabolic pathway gene polymorphisms with neural tube defects in Han population of Northern China

AssociationN=321Yulian Fang et al.(2018)· Child's Nervous System

A case-control study of 152 NTD patients and 169 controls in Han Chinese population identified three folate metabolism pathway SNPs associated with neural tube defects: rs2236225 in MTHFD1 (allele A, OR=1.500; AA genotype OR=2.862), rs1801133 in MTHFR (allele T, OR=1.552; TT genotype OR=2.344), and rs1801394 in MTRR (allele G, OR=1.533; GG genotype OR=2.355). The study demonstrates genetic variation in folate metabolism significantly affects NTD susceptibility.

Traits studied:NTDsNeural tube defects

PubMed DOI Metascience Observatory

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Variation in folate pathway genes contributes to risk of congenital heart defects among individuals with Down syndrome

AssociationN=243Adam E. Locke et al.(2010)· Genetic Epidemiology

This case-control study examined folate pathway gene variants in 121 DS-AVSD cases and 122 DS controls (no CHD). Tag SNPs in MTHFR, MTR, MTRR, CBS, and SLC19A1 were genotyped. SLC19A1 showed significant gene-level association with atrioventricular septal defect (P=0.01), with multiple tag SNPs nominally associated (OR 1.08-1.72). All significant SLC19A1 SNPs showed strong LD (r²≥0.80) with the nonsynonymous variant rs1051266 (c.80A>G, p.H27R). MTHFR c.1298A was over-transmitted to cases (P=0.05) and under-transmitted to controls (P=0.02), showing association in FBAT analysis (P=0.03 dominant, P=0.01 additive). These results suggest folate pathway disruption contributes to AVSD risk in Down syndrome individuals.

Traits studied:Atrioventricular septal defect (AVSD)Congenital heart defectsDown syndrome

rs162036

Key Literature Trait Associations

Spina bifida

Methionine Synthase Reductase Activity

Nonobstructive azoospermia

ClinVar annotation

Research that mentions this SNP (2)

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