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Hyperammonemia via the NAGS 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
NAGS 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9711NAGS81479 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

Urea cycle defects are characterized by (1) hyperammonemia, (2) encephalopathy, and (3) respiratory alkalosis. Five clinical disorders have been described involving defective urea cycle enzymes: ornithine transcarbamolase deficiency (OMIM 311250), carbamoyl phosphate synthetase I deficiency (OMIM 237300), argininosuccinate synthetase deficiency (OMIM 215700), argininosuccinate lyase deficiency (OMIM 207900), and arginase deficiency (OMIM 207800). A sixth cause of hyperammonemia is N-acetlyglutamate synthase (NAGS) deficiency (OMIM 237310; Bachmann et al. N Eng J Med 304:543, 1981). N-acetylglutamate is an essential activating cofactor for Carbamoyl Phosphate Synthetase I (CPS1) and, therefore, clinical signs of CPS1 and NAGS deficiencies are indistinguishable. Like CPS1 deficiency, two clinical presentations of NAGS deficiency are recognized: an acute neonatal hyperammonemia form and a delayed onset form (Haberle et al. Hum Mut 21:593-597, 2003). NAGS deficiency also presents with irritability and hyperammonemia leading to coma and death if untreated. Successful treatment with N-carbamylglutamate (NCG) has been reported (Bachmann et al. 1981).


Hyperammonemia due to N-Acetylglutamate Synthase (NAGS) deficiency is an autosomal recessive disorder. NAGS mutations are distributed throughout the entire coding region except for the mitochondrial targeting signal encoded by exon 1 (Caldovic et al. Hum Mut 28:754-759, 2007). The majority of mutations are missense, however nonsense and splice site mutations are known as well. A regulatory mutation (c.-3064C>A) in an enhancer region 3kb upstream of the NAGS coding sequence has also been identified, and patients homozygous for c.-3064C>A responded well to NCG treatment, showing enhanced ureagenesis (Heibel et al, Hum Mutat. 32:1153-60, 2011).

Clinical Sensitivity - Sequencing with CNV PGxome

Deficiency of N-Acetylglutamate Synthase is a rare cause of hyperammonemia. Approximately 20 causative mutations have been reported worldwide (Caldovic et al. Hum Mutat 28:754-759, 2007). Mutations in NAGS should be considered in patients with a high index of suspicion who have normal CPS1 enzyme activity and/or normal CPS1 gene sequencing results.

No gross deletions or duplications in NAGS have been reported (Human Gene Mutation Database).

Testing Strategy

This test provides full coverage of all coding exons of the NAGS 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).

Testing also includes the regulatory region surrounding the c.-3064C>A variant.

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

A plasma ammonia concentration of 150 μmol/L or higher, associated with a normal anion gap and a normal serum glucose concentration is a strong indication for the presence of a urea cycle defect (Summar, GeneReviews, 2011). Plasma citrulline levels can differentiate between defects in proximal urea cycle enzymes (low citrulline; ornithine transcarbamylase, carbamoyl phosphate synthetase I, N-acetylglutamate synthase) from distal enzymes (high citrulline; argininosuccinate synthetase, argininosuccinate lyase, and arginase). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in NAGS.


Official Gene Symbol OMIM ID
NAGS 608300
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Hyperammonemia, Type III AR 237310

Related Test

Urea Cycle Disorders Panel


  • Bachmann, C., et.al. (1981). "N-acetylglutamate synthetase deficiency: a disorder of ammonia detoxication." N Engl J Med 304(9): 543. PubMed ID: 7453791
  • Caldovic, L., et.al. (2007). "Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene." Hum Mutat 28(8): 754-9. PubMed ID: 17421020
  • Haberle, J., et.al. (2003). "Mutation analysis in patients with N-acetylglutamate synthase deficiency." Hum Mutat 21(6): 593-7. PubMed ID: 12754705
  • Heibel, et al, (2011). N-carbamylglutamate enhancement of ureagenesis leads to discovery of a novel deleterious mutation in a newly defined enhancer of the NAGS gene and to effective therapy. Hum Mutat. 32:1153-60. PubMed ID: 21681857
  • Human Gene Mutation Database (Bio-base).
  • Marshall L Summar (2011). "Urea Cycle Disorders Overview." PubMed ID: 20301396


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