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Homocystinuria, cblE Type, via the MTRR Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
MTRR 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11843MTRR81479 81479,81479 $990 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

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

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

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

Cobalamin (Cbl or vitamin B12) is an important cofactor in homocysteine metabolism and in branched-chain amino acid and odd-chain fatty acid catabolism. A series of inherited inborn errors of cobalamin metabolism have been identified, designated cblA through cblJ. In the cblE and cblG disorders, the formation of methionine via methylation of homocysteine is disrupted. Clinically and biochemically, the cblE and cblG disorders are indistinguishable (Watkins and Rosenblatt 2014).

The cblE disorder leads to homocystinuria, hyperhomocystinemia, and hypomethioninemia without methylmalonic aciduria. Clinically, most patients present in childhood with megaloblastic anemia, feeding difficulties, lethargy, hypotonia, cerebral atrophy and developmental delay, though some cases have been reported in which onset occurred during the first months of life or even in adulthood (Palanca et al. 2012; Watkins and Rosenblatt 2014; Zavadáková et al. 2002). Some patients have also exhibited ataxia, cerebral atrophy, neonatal seizures and blindness (Wilson et al 1999). One patient was reported that presented with Haemolytic-Uremic Syndrome as a newborn; bone marrow examination of this patient revealed megalobastic changes and hyperhomocystinemia (Palanca et al. 2012). The cblE disorder can be enzymatically distinguished from the cblG disorder as the activity of methionine synthase from cblG patients is deficient under all conditions tested, whereas the activity of methionine synthase from cblE patients is only deficient under limited reducing conditions (Wilson et al. 1998). Importantly, some cblD variant patients may have a very similar biochemical and clinical profile to cblE and cblG patients. These three disorders are best distinguished by complementation studies or direct gene sequencing (Carrillo-Carrasco et al. 2013).

Some cblE individuals may be identified by newborn screening programs, although this depends on the methods used by the screening laboratory and their ability to detect low levels of methionine. Therefore, complementation analysis and/or molecular genetic testing should still be considered for symptomatic individuals, even if newborn screening results were reported to be normal (Carrillo-Carrasco et al. 2013). A variety of treatment options have been explored for cblG patients, including folinic acid, vitamins B6 and B12, betaine and methionine. However, the outcome of treatment varies with each patient and even with early treatment, no therapy has been found that completely alleviates all symptoms (Carrillo-Carrasco et al. 2013).


Homocystinuria, cblE type is an autosomal recessive disorder, and MTRR is the only gene that is involved. To date, over 25 causative variants have been reported in the MTRR gene (Human Gene Mutation Database). The majority of reported pathogenic variants are missense and small deletions that lead to premature protein termination, although splice variants and small and gross insertions have also been reported. The variants are spread throughout the gene, with no reported mutational hotspots. No predominant variants have been reported, and for the most part, no clear genotype-phenotype correlations have been made. The Ser454Leu variant, however, has been suggested to lead to a milder, predominantly hematological presentation when found in the homozygous state (Vilaseca et al. 2003; Zavadáková et al. 2005).

The cblE disorder is caused by defects in the Methionine Synthase Reductase enzyme, which is responsible for the reductive activation of the Methionine Synthase enzyme. Methionine Synthase catalyzes the methylation of homocysteine, resulting in conversion to methionine. The clinical features of this disorder are thought to be caused by the accumulation of homocysteine and low levels of methionine in the blood as well as the "trapping" of the methyl donor 5-methyltetrahydrofolate (5-MTHF) in the Methionine Synthase enzyme. A lack of adequate levels of methionine leads to a decrease in the cellular level of the critical and widely used methyl group donor S-adenosylmethionine, and "trapping" of 5-MTHF prevents this metabolite from being available for other folate-dependent reactions (Watkins et al. 2002).

Clinical Sensitivity - Sequencing with CNV PGxome

Overall, the clinical sensitivity of this test is expected to be relatively high as the majority of confirmed cblE patients identified to date have been found to have MTRR variants that are detectable via DNA sequencing. In one study using cell lines from eight confirmed cblE patients, six patients were found to be compound heterozygous for two MTRR variants, while the other two patients were found to be heterozygous for a single MTRR variant but the second variant was not identified. This suggests an overall detection rate of ~88% (14 out of 16 alleles identified) (Wilson et al. 1999). In a second study of nine confirmed cblE patients, all patients were found to be compound heterozygous or homozygous for variants in the MTRR gene, giving an overall detection rate of 100% (Zavadáková et al. 2005).

It is difficult to estimate the clinical sensitivity of Copy Number Variant detection as to date, only one gross insertion has been reported in the MTRR gene (Wilson et al 1999), and no gross deletions have been reported. However, the clinical sensitivity appears to be relatively low.

Testing Strategy

This test provides full coverage of all coding exons of the MTRR gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Individuals with a positive newborn screening result for homocystinuria are good candidates for this test, particularly if they were also found to exhibit hypomethioninemia. Additionally, individuals that exhibit biochemical and clinical symptoms of cblE disorder are good candidates, as are family members of patients known to have MTRR variants. We will also sequence the MTRR gene to determine carrier status.


Official Gene Symbol OMIM ID
MTRR 602568
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Homocystinuria via the CBS Gene
Homocystinuria, cblG Type, via the MTR Gene
Methylmalonic Aciduria and Homocystinuria, cblD Type, via the MMADHC Gene
Methylmalonic Aciduria and Homocystinuria, cblF type, via the LMBRD1 Gene
Methylmalonic Aciduria and/or Homocystinuria via the CD320 Gene


  • Carrillo-Carrasco N, Adams D, Venditti CP. 2013. Disorders of Intracellular Cobalamin Metabolism. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301503
  • Human Gene Mutation Database (Bio-base).
  • Palanca D. et al. 2013. Jimd Reports. 8: 57-62. PubMed ID: 23430521
  • Vilaseca MA. et al. 2003. Journal of Inherited Metabolic Disease. 26: 361-9. PubMed ID: 12971424
  • 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.
  • Watkins D. et al. 2002. American Journal of Human Genetics. 71: 143-53. PubMed ID: 12068375
  • Wilson A. et al. 1998. American Journal of Human Genetics. 63: 409-14. PubMed ID: 9683607
  • Wilson A. et al. 1999. Human Molecular Genetics. 8: 2009-16. PubMed ID: 10484769
  • Zavadáková P. et al. 2002. Journal of Inherited Metabolic Disease. 25: 461-76. PubMed ID: 12555939
  • Zavadáková P. et al. 2005. Human Mutation. 25: 239-47. PubMed ID: 15714522


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

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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