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Severe MTHFR Deficiency via the MTHFR Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
MTHFR 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
7291MTHFR81479 81479,81479 $990 Order Options and Pricing

Pricing Comments

Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.


Genetic Counselors


  • McKenna Kyriss, PhD

Clinical Features and Genetics

Clinical Features

Deficiency of the 5,10-methylenetetrahydrofolate reductase (MTHFR deficiency) enzyme is the most commonly observed inborn error of folate metabolism (Kluijtmans et al. 1998; Froese et al. 2016). Patients diagnosed with severe MTHFR deficiency have enzyme activity levels that range from 0 to 20% of normal control levels (Kluijtmans et al. 1998; Sibani et al. 2000). Biochemically, these patients are found to have hyperhomocysteinemia and homocystinuria, elevated plasma S-adenosylhomocysteine and cystathionine, and low to normal levels of methionine in the plasma (Watkins and Rosenblatt 2014; Froese et al. 2016).

Clinically, the onset of symptoms generally occurs in the first two decades of life (Forges et al. 2010). Both neonatal and late-onset patients have been described. Neonatal patients tend to present with general muscular hypotonia, poor feeding and/or failure to thrive, lethargy and microcephaly. These patients may progress rapidly to coma or death via respiratory failure (Forges et al. 2010; Watkins and Rosenblatt 2014; Froese et al. 2016). Patients with late onset MTHFR deficiency generally present later in childhood or early in adulthood with behavioral problems, psychiatric symptoms, cognitive difficulties, progressive encephalopathy, ataxia, spasticity, and sometimes thromboses (Forges et al. 2010; Watkins and Rosenblatt 2014; Froese et al. 2016). Unlike some other disorders of folate metabolism, related methylation disorders and disorders of cobalamin metabolism, MTHFR deficient patients typically do not present with megaloblastic anemia, or methylmalonic aciduria (Watkins and Rosenblatt 2014). Clinical severity is highly variable (Watkins and Rosenblatt 2014).

Early treatment may help ameliorate or prevent symptoms. Although there is not a set treatment regimen for these patients, some combination of betaine and B vitamins (specifically folinic acid, cobalamin, pyridoxine, and riboflavin) has been shown to be helpful for some patients (Burda et al. 2015; Munoz et al. 2015; Froese et al. 2016).

Please note that we do not perform testing for the commonly reported MTHFR C677T and A1298C polymorphisms. See the Testing Strategy section for additional details on this limitation.


MTHFR deficiency is an autosomal recessive disorder, and the MTHFR gene is the only gene that is known to be involved. Over 100 variants have been reported to be associated with severe MTHFR deficiency (Froese et al. 2016; Human Gene Mutation Database). The variants are spread throughout the gene, with pathogenic variants reported in all exons with the exception of the first, non-coding exon. Approximately 70% of the variants are missense, ~25% are splicing or nonsense variants, with the remainder being small deletions, insertions or indels. Interestingly, missense variants are not distributed evenly throughout the gene. The 5’ end of the gene (which encodes the N-terminal catalytic domain) has more than twice the number of reported missense variants as the 3’ end of the gene (Burda et al. 2015; Froese et al. 2016). In general, most reported MTHFR variants are private pathogenic variants, although a few specific variants have been more commonly reported. For example, the c.474A>T (p.Gly158Gly) variant affects MTHFR splicing, and has been reported as a founder mutation in the Bukharian Jewish population (Ben-Shachar et al. 2012). Burda and colleagues (2015) reported the c.1141C>T (p.Arg377Cys) missense variant and c.1530G>A splice variant to be more commonly observed in their cohort.

A genotype-phenotype correlation does appear to exist in severe MTHFR deficient patients. In general, the severity of symptoms and age of onset tend to correlate with the amount of residual enzyme activity in that patient. Lower enzyme activity (particularly below ~1.5% of control levels) is generally associated with an earlier onset and more severe symptoms (Sibani et al. 2000; Forges et al. 2010; Burda et al. 2015).

The MTHFR enzyme catalyzes the NADPH-associated reduction of methylene-tetrahydrofolate (methylene-THF) to methyl-THF. Importantly, methyl-THF is the methyl group donor used in the conversion of homocysteine to methionine (Watkins and Rosenblatt 2014).

Clinical Sensitivity - Sequencing with CNV PG-Select

The clinical sensitivity of this test is expected to be high, as to date nearly all reported patients have had two pathogenic variants detectable via direct MTHFR sequencing (Goyette et al. 1995; Kluijtmans et al. 1998; Sibani et al. 2000; Sibani et al. 2003; Urreizti et al. 2010; Burda et al. 2015). In these studies, a total of 108 patients were reported with 211 alleles carrying a pathogenic variant, suggesting a clinical sensitivity of ~98%.

To date, no large deletions or duplications have been reported in MTHFR (Human Gene Mutation Database).

Testing Strategy

This test provides full coverage of all coding exons of the MTHFR gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Sequencing of the MTHFR gene is available only for patients with biochemical and/or clinical features consistent severe MTHFR deficiency, as described above. As recommended by the ACMG, ACOG and AHA, we do not offer testing for the MTHFR common polymorphisms c.665C>T and c.1286A>C (also known as C677T and A1298C) due to the limited clinical utility of such testing (Hickey et al. 2013; Levin and Varga 2016).

Indications for Test

Acceptable indications for testing: (1) Biochemical features consistent with severe MTHFR deficiency. This may include hyperhomocysteinemia, homocystinuria, low to normal plasma methionine levels, and elevated plasma S-adenosylhomocysteine and cystathionine. (2) Phenotypic features consistent with the clinical features for neonatal or late-onset severe MTHFR deficient patients. (3) A family member with known, severe MTHFR variants. We will sequence the MTHFR gene to determine carrier status for severe MTHFR variants.


Official Gene Symbol OMIM ID
MTHFR 607093
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Homocystinuria due to MTHFR Deficiency AR 236250

Related Tests

Disorders of Folate Metabolism and Transport Panel
Homocystinuria Panel


  • Ben-Shachar S. et al. 2012. Molecular Genetics and Metabolism. 107: 608-10. PubMed ID: 22947400
  • Burda P. et al. 2015. Human Mutation. 36: 611-21. PubMed ID: 25736335
  • Forges T. et al. 2010. Molecular Genetics and Metabolism. 100: 143-8. PubMed ID: 20356773
  • Froese D.S. et al. 2016. Human Mutation. 37: 427-38. PubMed ID: 26872964
  • Goyette P. et al. 1995. American Journal of Human Genetics. 56: 1052-9. PubMed ID: 7726158
  • Hickey S.E. et al. 2013. Genetics in Medicine. 15: 153-6. PubMed ID: 23288205
  • Human Gene Mutation Database (Bio-base).
  • Kluijtmans L.A. et al. 1998. European Journal of Human Genetics. 6: 257-65. PubMed ID: 9781030
  • Levin B.L., Varga E. 2016. Journal of Genetic Counseling. 25: 901-11. PubMed ID: 27130656
  • Munoz T. et al. 2015. Brain & Development. 37: 168-70. PubMed ID: 24726568
  • Sibani S. et al. 2000. Human Mutation. 15: 280-7. PubMed ID: 10679944
  • Sibani S. et al. 2003. Human Mutation. 21: 509-20. PubMed ID: 12673793
  • Urreizti R. et al. 2010. Clinical Genetics. 78: 441-8. PubMed ID: 20236116
  • Watkins and Rosenblatt. 2014. Inherited Disorders of Folate and Cobalamin Transport and Metabolism. In: Valle D, Beaudet A.L., Vogelstein B, et al., editors. New York, NY: McGraw-Hill. OMMBID.


Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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