The methylenetetrahydrofolate reductase (MTHFR) gene provides instructions for making an enzyme that plays a fundamental role in processing folate, a B-vitamin. This MTHFR enzyme is responsible for converting dietary folate and synthetic folic acid into its active form, L-methylfolate or 5-MTHF, which the body can readily use. When variations, often called polymorphisms, occur in this gene, the efficiency of the resulting enzyme may be reduced, impacting this metabolic process.
Understanding the MTHFR Gene and Variants
The MTHFR gene is central to the methylation cycle, a biochemical process that affects DNA synthesis, repair, and the metabolism of the amino acid homocysteine. The enzyme produced by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate. This active folate form is then used to convert homocysteine back into methionine, a precursor for other important molecules in the body.
Genetic variations in the MTHFR gene can slow down this conversion process, potentially leading to a buildup of homocysteine in the bloodstream. While dozens of variations exist, two common single nucleotide polymorphisms (SNPs) are routinely tested: C677T and A1298C.
The C677T variant involves a change from a Cytosine (C) to a Thymine (T) at position 677. Individuals carrying two copies of the C677T variant (TT) typically experience the most significant reduction in enzyme activity, sometimes up to 70% less efficient than the non-variant form. The A1298C variant, where an Adenine (A) changes to a Cytosine (C) at position 1298, generally results in a less severe reduction in enzyme efficiency.
Who Should Consider MTHFR Testing
Genetic testing for the common MTHFR variants is not recommended for the general population as a routine screening measure. Major medical organizations advise against widespread testing because the presence of the variants alone does not usually indicate disease or require specific treatment. Most individuals with these common variants maintain normal health and homocysteine levels, especially when folate intake is adequate.
Testing is generally reserved for specific clinical scenarios where a physician believes the results could influence treatment or management. This includes the presence of unexplained, elevated levels of homocysteine in the blood, known as hyperhomocysteinemia. Although high homocysteine can be caused by other factors, the MTHFR genotype can help determine a potential genetic contribution.
Testing is also indicated when a patient is prescribed certain medications, such as methotrexate, a drug used to treat conditions like cancer and rheumatoid arthritis. Since the MTHFR enzyme helps the body process this medication, knowing a patient’s genotype may help a doctor determine an appropriate dosing strategy.
Testing for MTHFR variants is not currently recommended for the routine evaluation of cardiovascular disease risk, recurrent pregnancy loss, or blood clot risk. In these situations, measuring homocysteine levels directly is often considered more informative than identifying the genetic variant itself.
The Different Methods of MTHFR Testing
There are two primary avenues for obtaining MTHFR genetic information: clinical diagnostic testing and direct-to-consumer (DTC) genetic testing. Clinical testing is ordered by a medical professional and is processed by a certified laboratory. The sample is typically collected via a blood draw, though a cheek swab or saliva sample can also be used.
For clinical testing, a physician will submit a lab order, and the process is often covered by health insurance if a specific medical necessity, or clinical indication, is established. This method ensures that the test specifically targets the relevant MTHFR variants (C677T and A1298C) using validated procedures. The results from a clinical lab are typically delivered directly to the ordering physician for interpretation.
Direct-to-consumer testing, offered by companies like 23andMe or AncestryDNA, is the second common method. These services allow individuals to order a genetic kit online, collect a saliva or cheek swab sample at home, and mail it back to the company. DTC tests often analyze hundreds of thousands of genetic markers, including the MTHFR variants, as part of a broader health or ancestry report.
While DTC testing is convenient and often less expensive than a full clinical panel, its results are considered informational rather than diagnostic. The technology used by DTC companies may not be as comprehensive as clinical-grade sequencing. If a variant is detected, a physician may require a confirmatory clinical test before making any medical decisions.
Interpreting the Test Results
A test report for MTHFR will identify the genotype for both the C677T and A1298C variants. The normal or “wild type” genotype means no variant was detected in the specific position on either copy of the gene inherited from the parents. For C677T, this is reported as CC, and for A1298C, it is reported as AA.
The term heterozygous indicates that the individual inherited one copy of the variant from one parent and one normal copy from the other parent. A heterozygous result for the C677T variant would be reported as CT, and for A1298C, it would be AC. Having a single heterozygous variant typically results in only a mild reduction in the enzyme’s function.
Homozygous means the individual inherited two copies of the variant, one from each parent, resulting in the greatest reduction in enzyme efficiency. These are reported as TT for the C677T variant and CC for the A1298C variant. Individuals with the homozygous TT genotype for C677T are known to have the most significantly impaired enzyme function, which can be as low as 30% of normal activity.
A final combination, compound heterozygous, is reported when a person has one copy of the C677T variant and one copy of the A1298C variant (CT/AC). This combination is often considered to have a functional impact similar to the homozygous C677T genotype, leading to a notable reduction in the MTHFR enzyme’s efficiency. Understanding these terms is paramount, as they directly correlate with the degree of potential enzyme inefficiency.