Rare Nephrology News

Disease Profile

MTHFR gene variant

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

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ICD-10

#N/A

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Methylenetetrahydrofolate reductase variant

Summary

MTHFR is a gene. We all carry two copies of MTHFR. MTHFR tells our body how to create an enzyme involved in breaking down the amino acid homocysteine.[1][2][3] As is true for any gene, the DNA code of the MTHFR gene can vary. When we identify a part of the sequence that varies, we call it a "variant." Genetic research aims to identify specific variants that cause harm or benefit to health.

There are two MTHFR gene variants, called C677T and A1298C, that have been an active area of study. These variants are common. In America, about 25% of people who are Hispanic, and 10-15% of people who are Caucasian have two copies of C677T.[4]

Studies have found that women with two C677T gene variants have an increased risk for having a child with a neural tube defect.[4]

Very high homocysteine levels rarely result from having two common variants alone. People with very high homocysteine levels should be carefully evaluated for other factors known to affect homocysteine. Doing so may bring to light dietary deficiencies, thyroid disease, diabetes, high cholesterol, or life-style factors (physical inactivity, smoking and obesity) which can impact homocystine levels. If high levels of homocysteine cannot be explained by these factors, a consultation with a genetics professional may be helpful in identifying rare genetic causes of the high homocysteine.[5] To learn more about rare genetic causes, visit: Homocystinuria due to MTHFR Deficiency.

Symptoms

People with common MTHFR variants can have normal or elevated levels of homocysteine in their blood or urine. MTHFR variants and elevated homocysteine levels have been studied as risk factors for a number of health conditions.

When thinking about risk factors it is important to not only think about if the variants put you at risk for a condition, but if so, how much risk. You will find many studies on MTHFR and health risks. For most of these, evidence is lacking regarding an association.[6]

One condition that is widely recognized to be associated with the common MTHFR variants is neural tube defects. Studies suggest that women with two C677T gene variants are twice as likely to have a child with a neural tube defect.[4] However, because neural tube defects are rare, their actual risk is still far less than 1% (0.14%).[7][8] You can learn more about neural tube defects and health risks by visiting the March of Dimes Web site.

Risks associated with having one C677T and one A1298C is the same, or possibly slightly lower than, that of having two C677T gene changes.[9][4]

For the vast majority of people the overall risk associated with the common MTHFR variants is small. So small, that having them does not change treatment. This is why testing for the variants is not recommended, unless a person has very high homocysteine levels. It is important to keep in mind that neural tube defects have many other risk factors.

Very high homocysteine levels rarely result from having the common variants alone. People with very high homocysteine levels should be carefully evaluated for other factors known to affect homocysteine, such as:[10][11][12]

Low thyroid hormones (hypothyroidism)
Chronic conditions (obesity, diabetes, high cholesterol, physical inactivity, high blood pressure)
Medications (atorvastatin, fenofibrate, methotrexate, andnicotinic acid)
Smoking
Advanced age

High homocysteine levels can also result from dietary deficiencies of folate, vitamin B6, and vitamin B12. It is very important to diagnose vitamin B12 deficiencies, as high dose folic acid supplements can mask B12 deficiencies, and put people at risk for serious and irreversible symptoms. Learn more about B12 deficiency.

If high levels of homocysteine can not be explained by factors such as those listed above, a consultation with a genetics professional may be helpful in identifying rare genetic causes of the high homocysteine.[5] To learn more about rare genetic causes, visit: Homocystinuria due to MTHFR Deficiency.

Diagnosis

Genetic testing is available for MTHFR gene variants, however testing is rarely recommended.

The American Congress of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics recommends against testing for common MTHFR gene variants. Common MTHFR gene variants have not been proven to be a concerning risk factor for blood clots, pregnancy loss, or other negative pregnancy outcomes.[14]

The American Heart Association recommends against testing for the common MTHFR gene variants or homocysteine as a screen for increased risk of cardiovascular conditions.[15][9][14] The Association does not consider MTHFR a major risk factor for heart disease.

The College of American Pathologists, the American College of Medical Genetics, and the American Heart Association recommend against testing for C677T and A1298C in people with blood clots. This is because results have little impact on a persons medical management.[15][9][4]

Some people who contact GARD have already had testing for MTHFR gene variants and want to know if the variants could be causing their symptoms. Any individual who suspects that a disease or disorder is related to MTHFR deficiency should talk to their doctor about testing for fasting homocysteine levels in the blood.[4]

If the fasting blood homocysteine level is high, then the patient should seek medical advice from an expert doctor in this field who can address the possible medical implications. If the fasting homocysteine level in the blood is normal, then it is unlikely that the person's symptoms are due to the MTHFR genetic variation.

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

    Treatment

    Having MTHFR gene variants alone does not impact treatment. If a person has high homocysteine levels they should be carefully evaluated to identify all causes. Very high homocysteine levels rarely result from having the common variants alone. People with very high homocysteine levels should be carefully evaluated for other factors known to affect homocysteine, such as:[10][11][12]

    Low thyroid hormones (hypothyroidism)
    Chronic conditions (obesity, diabetes, high cholesterol, physical inactivity, high blood pressure)
    Medications (atorvastatin, fenofibrate, methotrexate, andnicotinic acid)
    Dietary deficiencies (folate, vitamin B6, vitamin B12)
    Smoking
    Advanced age

    Treatments and life-style changes are given based upon the patient's circumstances. As mentioned above, homocysteine levels can rise in people with and without MTHFR gene variants if they lack folate, choline, or B vitamins (B12B6, and riboflavin).[10][11] It is very important to diagnose vitamin B12 deficiencies, as high dose folic acid supplements can mask B12 deficiencies, and put people at risk for serious and irreversible symptoms. Visit the Office of Dietary Supplements Web page for more on B12. People with concerns about their nutrition should speak with a healthcare professional. Supplements may be recommended if the person is found to have a nutritional deficiency.[3][10]

    Current clinical guidelines do not recommend changes in prenatal care or prenatal vitamins based upon MTHFR gene variant status alone. Women of childbearing age should take the standard dose of folate supplementation to reduce the risk of neural tube defects.[4][14][16] Women with a previous child with a neural tube defect or a family history of neural tube defect should talk to their doctors about requirements for extra folate supplementation.[14]

    We recommend you speak with a trusted healthcare professional before taking any supplement.

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Organizations Providing General Support

        Learn more

        These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

        Where to Start

          In-Depth Information

          • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
          • MTHFR is a part of pathways acted on by certain drugs, making it a gene of research interest. A threshold of evidence must be reached before research data can be used in patient care. The Pharmacogenomics Knowledgebase (PharmGKB) is a NIH-funded resource that can help you gauge the status of current data and locate trustworthy drug dosing guidelines. Visit the PharmGKB MTHFR Summary and PharmGKB MTHFR Clinical Annotation Page. You may need to register to view the pages but registration is free.
          • PubMed is a searchable database of medical literature and lists journal articles that discuss MTHFR gene variant. Click on the link to view a sample search on this topic.

            Selected Full-Text Journal Articles

              References

              1. MTHFR. Genetics Home Reference (GHR). November, 2014; https://ghr.nlm.nih.gov/gene/MTHFR.
              2. Varga EA, Sturm AC, Misita CP & Moll S. Homocysteine and MTHFR Mutations: Relation to Thrombosis and Coronary Artery Disease. Circulation. 2005; 111:e289-e293. https://circ.ahajournals.org/content/111/19/e289.full.
              3. Rosenson RS & Kang DS. Overview of homocysteine. UpToDate. July 21 2017; https://www.uptodate.com/contents/overview-of-homocysteine.
              4. Dean L. Methylenetetrahydrofolate Reductase Deficiency. Medical Genetics Summaries. NCBI; Last updated October 27, 2016; https://www.ncbi.nlm.nih.gov/books/NBK66131/. Accessed 5/3/2017.
              5. Homocystinuria due to deficiency of N(5,10)-Methylenetetrahydrofoloate reductase activity. Online Mendelian Inheritance in Man. 2007; https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=236250.
              6. Liew SC & Gupta ED. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. Eur J Med Genet. January 2015; 58(1):1-10. https://www.ncbi.nlm.nih.gov/pubmed/25449138.
              7. Botto LD, Yang Q. 5,10-methylenetetrahydrofolate reductase gene variants and congenital anomalies: A HuGE review. American Journal of Epidemiology. 2000; 151(9):862–877. Accessed 4/17/2018.
              8. Williams J, Mai CT, Mulinare J, Isenburg J, Flood TJ, Ethen M, Frohnert B, Kirby RS; Centers for Disease Control and Prevention. Updated estimates of neural tube defects prevented by mandatory folic Acid fortification United States, 1995-2011. MMWR Morb Mortal Wkly Rep. 2015 Jan 16; 64(1):1-5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4584791/. Accessed 4/18/2018.
              9. Hickey SE, Curry CJ, Toriello HV.. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. February 2013; 15(2):153-156. https://www.ncbi.nlm.nih.gov/pubmed/23288205.
              10. Folate. Linus Pauling Institute Micronutrient Information Center. 2014; https://lpi.oregonstate.edu/mic/vitamins/folate#disease-treatment.
              11. American Association for Clinical Chemistry. Homocysteine. LabTestsOnline. April 30, 2014; https://labtestsonline.org/understanding/analytes/homocysteine/tab/test.
              12. Varga E and Moll S. Homocysteine and MTHFR Mutations. Circulation. 2015; 132:e6-e9. https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.114.013311.
              13. Homocystinuria. Genetics Home Reference. March, 2016; https://ghr.nlm.nih.gov/condition/homocystinuria.
              14. Levin BL, Varga E. MTHFR: Addressing Genetic Counseling Dilemmas Using Evidence-Based Literature. J Genet Couns.. 2016 Oct; 25(5):901-11:https://www.ncbi.nlm.nih.gov/pubmed/27130656.
              15. MTHFR Mutation. Lab Tests Online. April 2014; https://labtestsonline.org/understanding/analytes/mthfr/tab/test.
              16. Stover PJ, MacFarlane AJ, Field MS. Bringing clarity to the role of MTHFR variants in neural tube defect prevention. Am J Clin Nutr. May 13, 2015; 101(6):1111-1112. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441815/.
              17. Homocysteine. American Academy of Family Physicians. 2006; https://familydoctor.org/online/famdocen/home/articles/249.html. Accessed 5/13/2009.
              18. Tran M and Spencer FA. Thromboepidemiology: Identifying patients with heritable risk for thrombin-mediated thromboembolic events. American Heart Journal. 2005; 149(1 Suppl):s9-18. https://www.ncbi.nlm.nih.gov/pubmed/15644796.
              19. Homocystinuria. Genetics Home Reference (GHR). March, 2016; https://ghr.nlm.nih.gov/condition=homocystinuria.
              20. Wilcken B & cols. Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): Findings from over 7000 newborns from 16 areas world wide. J Med Genet 2003; 40(8):619–25. https://www.ncbi.nlm.nih.gov/pubmed/12920077.
              21. MTHFR Variant Analysis. Cleveland Clinic Laboratories. https://clevelandcliniclabs.com/assets/pdfs/technical-briefs/mthfr-81692.pdf.

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