Methylenetetrahydrofolate Reductase (MTHFR) 2 Variants
Ordering Recommendation

Determine genetic cause for hyperhomocysteinemia and potential sensitivity to antifolate drugs. Test is not recommended for women who have recurrent pregnancy loss, thrombophilia screening, or neural tube defect risk assessment.

Polymerase Chain Reaction/High Resolution Melt Analysis
2-6 days
New York DOH Approval Status
This test is New York DOH approved.
Submit With Order
ARUP Consult®
Disease Topics
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. 
Ambient: 72 hours; Refrigerated: 2 weeks; Frozen: 1 month 
Reference Interval
Negative: Neither of the common MTHFR gene variants tested, c.665C>T (previously designated C677T) and c.1286A>C (previously designated A1298C), were detected. Other causes of elevated homocysteine levels, coronary heart disease, or thrombosis were not assessed. This genotype is associated with a normal folate metabolism.
Interpretive Data
Background Information for Methylenetetrahydrofolate Reductase (MTHFR) 2 Variants:
Variants in the MTHFR gene (c.665C>T and c.1286A>C) correlate with reduced enzyme activity; however, only homozygotes for the c.665C>T variant have been significantly associated with elevated plasma homocysteine levels and with an increased risk for premature cardiovascular disease. These individuals may also show toxicity from medications (ie, methotrexate) that affect folate metabolism.
The allele frequency of c.665C>T is 0.35 in European Caucasians and 0.12 in African Americans. The allele frequency of c.1286A>C is 0.31 in European Caucasians and 0.15 in African Americans.
Autosomal recessive.
Homozygosity for MTHFR gene mutation c.665C>T.
Mutations Tested:
c.665C>T (previously designated C677T); p.Ala222Val and c.1286A>C (previously designated A1298C); p.Glu429Ala.
Clinical Sensitivity:
Undefined. Sensitivity is dependent upon multiple contributing factors.
Polymerase chain reaction followed by high resolution melt analysis.
Analytical Sensitivity & Specificity
: 99 percent.
Only the two MTHFR gene mutations (c.665C>T and c.1286A>C) will be targeted. Diagnostic errors can occur due to rare sequence variations.

Compliance Statement C: The performance characteristics of this test were validated by ARUP Laboratories. The U.S. Food and Drug Administration (FDA) has not approved or cleared this test. However, FDA approval or clearance is currently not required for clinical use of this test. The results are not intended to be used as the sole means for clinical diagnosis or patient management decisions. ARUP is authorized under Clinical Laboratory Improvement Amendments (CLIA) and by all states to perform high-complexity testing. Counseling and informed consent are recommended for genetic testing. Consent forms are available online.

Component Test Code*Component Chart NameLOINC
0055657MTHFR Mutation: c.665C>T28005-7
0055658MTHFR Mutation: c.1286A>C28060-2
0055660MTHFR Interpretation21709-1
2001331MTHFR PCR Specimen31208-2
* 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