Ordering Recommendation

Examines one genetic factor that contributes to hyperhomocysteinemia. Test is not recommended for recurrent pregnancy loss, thrombophilia screening, or neural tube defect risk assessment, or for family members of individuals with known MTHFR variants.

New York DOH Approval Status

This test is New York state approved.

Specimen Required

Patient Preparation

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

Specimen Preparation

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

Storage/Transport Temperature


Unacceptable Conditions

Plasma or serum. Heparinized specimens. Frozen specimens in glass collection tubes.


Ambient: 72 hours; Refrigerated: 1 week; Frozen: 1 month


Polymerase Chain Reaction/Fluorescence Monitoring




2-6 days

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.
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.
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)


Hotline History


CPT Codes



Component Test Code* Component Chart Name LOINC
0055657 MTHFR Variant: c.665C>T 28005-7
0055658 MTHFR Variant: c.1286A>C 28060-2
0055660 MTHFR Interpretation 21709-1
2001331 MTHFR PCR Specimen 31208-2
* Component test codes cannot be used to order tests. The information provided here is not sufficient for interface builds; for a complete test mix, please click the sidebar link to access the Interface Map.


  • MTHFR DNA assay
Methylenetetrahydrofolate Reductase (MTHFR) 2 Variants