Argininemia via the ARG1 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code TestIndividual Gene PriceCPT Code Copy CPT Codes
552 ARG1$710.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

In patients previously diagnosed with elevated serum arginine and decreased enzyme activity, test sensitivity should be very high. For example, in eleven argininemia patients Uchino et al. (1995) detected 21 of 22 possible mutant alleles. Similarly, Cardoso et al. (1999) detected 2 pathogenic alleles in each of 4 patients, and Carvalho et al. (2012) detected 2 pathogenic alleles in each of 16 patients. Overall, this suggests a clinical sensitivity of ~98%.

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Deletion/Duplication Testing via aCGH

Test Code TestIndividual Gene PriceCPT Code Copy CPT Codes
600 ARG1$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

Overall, large duplications and deletions appear to be relatively rare in the ARG1 gene. To our knowledge, only two large deletions have been reported in the literature to date (Wang et al. 2012; Human Gene Mutation Database).

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Clinical Features

Urea cycle defects are characterized by hyperammonemia, encephalopathy and respiratory alkalosis (Brusilow and Horwich 2014). Eight clinical disorders have been described involving defective urea cycle enzymes or transporter proteins: N-acetylglutamate synthase deficiency, carbamoyl phosphate synthetase I deficiency, ornithine transcarbamolase deficiency, argininosuccinate synthetase deficiency (also known as citrullinemia type I), argininosuccinate lyase deficiency, arginase deficiency, citrin deficiency (also known as citrullinemia type II) and hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome (Ah Mew et al. 2015). Untreated patients with arginase deficiency develop spastic paraplegia, epileptic seizures, and severe mental retardation (Cederbaum et al. 1977; Wong et al. 2014). Hyperammonemia due to arginase deficiency is usually less severe than that arising from defects in the proximal urea cycle enzymes. Early growth and development are generally normal until ages 1 to 3 years when symptoms begin to be evident (Wong et al. 2014).  An arginine restricted diet along with sodium benzoate to scavenge ammonia has been found to be effective treatment (Bernar et al. 1986; Wong et al. 2014).


Argininemia is an autosomal recessive disorder caused by pathogenic sequence variants in the ARG1 gene, which is located at chromosome 6q23. ARG1 pathogenic variants are the only known cause of argininemia, and thus far over 50 pathogenic ARG1 sequence variants have been reported in the literature. Missense, nonsense and small deletion variants are the predominant types of disease causing variants in the ARG1 gene, though splice variants, small insertions, duplication and indels, as well as gross deletions, have all been reported (Human Gene Mutation Database).

ARG1 encodes arginase, a liver-specific enzyme that generates urea and ornithine from arginine in the last step of the urea cycle. The ARG1 gene product is also active in red blood cells.  

Testing Strategy

This test involves bidirectional Sanger sequencing using genomic DNA of all coding exons of the ARG1 gene plus ~20 bp of flanking non-coding DNA on each side. Note that this test includes coverage for the pathogenic deep intronic variant designated c.306-611T>C. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.

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 (Ah Mew et al. 2015). Plasma citrulline levels can differentiate between defects in proximal urea cycle enzymes (low citrulline; OTC and carbamoyl phosphate synthetase) from distal enzymes (high citrulline; argininosuccinate synthetase, argininosuccinate lyase, and arginase). Individuals with elevated serum arginine levels or reduced arginase activity in red cells are candidates for ARG1 testing. Family members of patients known to have ARG1 variants are also good candidates for this test. We will also sequence the ARG1 gene to determine carrier status.


Official Gene Symbol OMIM ID
ARG1 608313
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Arginase Deficiency AR 207800

Related Test

Urea Cycle Disorders Sequencing Panel


Genetic Counselors
  • Ah Mew N. et al. 2015. Urea Cycle Disorders Overview. 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: 20301396
  • Bernar J. et al. 1986. The Journal of Pediatrics. 108: 432-5. PubMed ID: 3950825
  • Brusilow S.W. and Horwich A.L. 2014. Urea Cycle Enzymes. Online Metabolic & Molecular Bases of Inherited Disease, New York, NY: McGraw-Hill.
  • Cardoso M.L. et al. 1999. Human Mutation. 14: 355-6. PubMed ID: 10502833
  • Carvalho D.R. et al. 2012. Gene. 509: 124-30. PubMed ID: 22959135
  • Cederbaum S.D. et al. 1977. The Journal of Pediatrics. 90: 569-73. PubMed ID: 839368
  • Human Gene Mutation Database (Bio-base).
  • Uchino T. et al. 1995. Human Genetics. 96: 255-60. PubMed ID: 7649538
  • Wang J. et al. 2012. Molecular Genetics and Metabolism. 106: 221-230. PubMed ID: 22494545
  • Wong D. et al. 2014. Arginase Deficiency. 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.
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing Via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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Ordering Options

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.
  • The first four pages of the requisition form must accompany all specimens.
  • Billing information is on the third and fourth pages.
  • Specimen and shipping instructions are listed on the fifth and sixth pages.
  • All testing must be ordered by a qualified healthcare provider.


(Delivery accepted Monday - Saturday)

  • Collect 3-5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10-20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is good for up to 48 hours.
  • If refrigerated, blood specimen is good for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • NextGen Sequencing Tests: Send in screw cap tube at least 10 µg of purified DNA at a concentration of at least 50 µg/ml
  • Sanger Sequencing Tests: Send in a screw cap tube at least 15 µg of purified DNA at a concentration of at least 20 µg/ml. For tests involving the sequencing of more than three genes, send an additional 5 µg DNA per gene. DNA may be shipped at room temperature.
  • Deletion/Duplication via aCGH: Send in screw cap tube at least 1 µg of purified DNA at a concentration of at least 100 µg/ml.
  • Whole-Genome Chromosomal Microarray: Collect at least 5 µg of DNA in TE (10 mM Tris-cl pH 8.0, 1mM EDTA), dissolved in 200 µl at a concentration of at least 100 ng/ul (indicate concentration on tube label). DNA extracted using a column-based method (Qiagen) or bead-based technology is preferred.


(Delivery accepted Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Ship at least two T25 flasks of confluent cells.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We do not culture cells.