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EPIC CODE: LAB739 Methylenetetrahydrofolate Reductase (MTHFR) 2 Variants

Additional Codes

Sunquest:  MTHFR
ARUP:       0055655


UnityPoint Health Methodist for processing
UnityPoint Health Pekin for processing
UnityPoint Health Proctor for processing

Performed at ARUP, Salt Lake City


Ordering Recommendations

Determines genetic contribution to hyperhomocysteinemia for individuals with elevated plasma homocysteine. Not recommended for recurrent pregnancy loss, thrombophilia screening, neural tube defect risk assessment, or testing of family members of individuals with identified MTHFR variants.


Lavender (EDTA), pink (K2EDTA), or yellow (ACD Solution A or B).

Transport 3 mL whole blood. (Min: 1 mL)


Ambient: 72 hours; Refrigerated: 2 weeks; Frozen: 1 month

Unacceptable Conditions

Plasma or serum. Heparinized specimens.

Day(s) Performed


Duration of Testing

2-6 days


Polymerase Chain Reaction and Fluorescence Monitoring


Component Test Code* Component Chart Name LOINC
0055657 MTHFR Mutation: c.665C>T 28005-7
0055658 MTHFR Mutation: c.1286A>C 28060-2
0055660 MTHFR Interpretation 21709-1
2001331 MTHFR PCR Specimen 31208-2

Reference Interval

Negative: Neither of the MTHFR variants tested, c.665C>T (previously designated C677T) and c.1286A>C (previously designated A1298C), were detected. Other causes of elevated homocysteine levels were not evaluated.

Interpretive Data

Background Information for Methylenetetrahydrofolate Reductase (MTHFR), 2 Variants:
Variants in the MTHFR gene may reduce enzyme activity contributing to hyperhomocysteinemia. Although hyperhomocysteinemia was previously reported to be a risk factor for many conditions, especially venous thrombosis and cardiovascular disease, recent meta-analysis casts doubt on whether lifelong moderate homocysteine elevation has an effect on cardiovascular disease. The American College of Medical Genetics Practice Guidelines indicate that individuals with elevated homocysteine and two copies of the c.665C>T variant have an odds ratio of 1.27 for venous thromboembolism. Thus, they recommend MTHFR genotyping not be ordered as part of a routine evaluation for recurrent pregnancy loss or thrombophilia due to questionable clinical significance.
Incidence: The allele frequency of the c.665C>T variant is 0.35 in European Caucasians, 0.5 in Hispanics, and 0.12 in African Americans.
Inheritance: Autosomal recessive; two copies of the c.665C>T variant may be a contributing factor to hyperhomocysteinemia.
Variants Tested: c.665C>T(p.Ala222Val) and c.1286A>C(p.Glu429Ala). (legacy names, C677T and A1298C, respectively).
Clinical Sensitivity: Undefined; hyperhomocysteinemia is caused by genetic, physiologic and environmental factors. MTHFR variants are only one contributing factor.
Methodology: Polymerase chain reaction (PCR) and fluorescence monitoring.
Analytical Sensitivity & Specificity: 99 percent.
Limitations: Only two MTHFR gene variants (c.665C>T and c.1286A>C) are tested. Diagnostic errors can occur due to rare sequence variations. 

This test was developed and its performance characteristics determined by ARUP Laboratories. It has not been cleared or approved by the US Food and Drug Administration. This test was performed in a CLIA certified laboratory and is intended for clinical purposes.

Counseling and informed consent are recommended for genetic testing. Consent forms are available online.

Compliance Category

Laboratory Developed Test (LDT)