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Transcobalamin II Deficiency via the TCN2 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
11861 TCN2 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11861TCN281479 81479,81479 $890 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.

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 backbone).

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

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

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days 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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • McKenna Kyriss, PhD

Clinical Features and Genetics

Clinical Features

Transcobalamin II is an inherited disorder that results from defective transport of cobalamin (vitamin B12) into tissues and cells (Li et al. 1994a; Carrillo et al. 2013; Ünal et al. 2015). Onset is in early infancy, and is characterized by gastrointestinal symptoms such as vomiting and diarrhea, hematological deficiencies (including megaloblastic anemia and pancytopenia), failure to thrive, and eventual neurological complications in some patients, especially if treatment is delayed. Neurological complications can include developmental delay, seizures and cerebellar disturbances. Retinopathy due to macular degeneration has also been reported (Li et al. 1994a; Häberle et al. 2009; Schiff et al. 2010; Carrillo et al. 2013; Ünal et al. 2015). Metabolic test results reveal that these patients have normal serum cobalamin levels, but low serum transcobalamin. Most also are found to have methylmalonic aciduria and homocystinuria (Schiff et al. 2010; Carrillo et al. 2013; Ünal et al. 2015).

Treatment, usually with intramuscular injections of hydroxocobalamin, can help with hematological and biochemical disburbances, but may not completely prevent neurological complications (Namour et al. 2003; Schiff et al. 2010; Ünal et al. 2015). Earlier treatment seems to result in a better outcome for these patients (Schiff et al. 2010).

Genetics

Transcobalamin II deficiency is an autosomal recessive disorder caused by defects in the TCN2 gene, which is located at chromosome 22q12.2. Over 25 pathogenic variants have been reported in the TCN2 gene, nearly all of which have been nonsense, splicing, or protein truncating variants, or larger copy number variants (Human Gene Mutation Database). One single amino acid deletion has been reported (His167del); this amino acid resides in the transcobalamin receptor binding region (Schiff et al. 2010). Thus far, no missense variants have been associated with transcobalamin II deficiency. Most reported TCN2 variants seem to be private, familial variants.

The transcobalamin II (TC II) protein is responsible for the transport of cobalamin from the blood into the cells via receptor-mediated endocytosis. Cobalamin-associated TC II enters the lysosomes where the TC II protein is degraded, freeing the cobalamin moiety for downstream reactions (Li et al. 1994a; Häberle et al. 2009).

Clinical Sensitivity - Sequencing with CNV PGxome

Based on collective totals of transcobalamin II deficient patients reported in the literature, the clinical sensitivity of TCN2 sequencing is estimated to be ~73% (29 pathogenic TCN2 alleles out of 40 total alleles, with only one patient counted if multiple family members were affected) (Li et al. 1994a; Li et al. 1994b; Namour et al. 2003; Prasad et al. 2008; Häberle et al. 2009; Ratschmann et al. 2009; Nissen et al. 2010; Schiff et al. 2010; Ünal et al. 2015; Pupavac et al. 2016). The remaining ~27% of alleles contained exonic or larger deletions that may not be detected by sequencing.

Testing Strategy

This test provides full coverage of all coding exons of the TCN2 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

Infants with hematological changes such as pancytopenia and megaloblastic anemia are good candidates for this test, especially if they have normal serum cobalamin levels, but low serum transcobalamin levels. Patients with methylmalonic aciduria and homocystinuria and no molecular diagnosis are also good candidates for this test, particularly if they also have low serum transcobalamin levels. Testing is also indicated for family members of patients with known TCN2 mutations. We will also sequence the TCN2 gene to determine carrier status.

Gene

Official Gene Symbol OMIM ID
TCN2 613441
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Transcobalamin II Deficiency AR 275350

Citations

  • Carrillo N. et al. 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
  • Häberle J. et al. 2009. Journal of Human Genetics. 54: 331-4. PubMed ID: 19373259
  • Human Gene Mutation Database (Bio-base).
  • Li et al. 1994a. PubMed ID: 7849710
  • Li et al. 1994b. PubMed ID: 7980584
  • Namour et al. 2003. PubMed ID: 14632784
  • Nissen et al. 2010. PubMed ID: 20607612
  • Prasad et al. 2008. PubMed ID: 18956254
  • Pupavac et al. 2016. PubMed ID: 26827111
  • Ratschmann et al. 2009. PubMed ID: 19581117
  • Schiff et al. 2010. PubMed ID: 20352340
  • Ünal S. et al. 2015. Turkish Journal of Haematology. 32: 317-22. PubMed ID: 25914105

Ordering/Specimens

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


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

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