Primary Macronodular Adrenal Hyperplasia via the ARMC5 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1899 ARMC5$910.00 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

The clinical sensitivity of this gene is difficult to predict due to the limited number of studies, but one review has suggested that bilateral macronodular adrenal hyperplasia may be present in 50% of apparently sporadic cases (De Venanzi et al. 2014). Sanger sequencing should be able to detect the majority of reported ARMC5 pathogenic variants, but generally will not be able to detect gross deletions/duplications.

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Clinical Features

Primary macronodular adrenal hyperplasia (PMAH) leads to excess cortisol secretion and rarely, Cushing syndrome. It often goes unrecognized and is usually detected as an adrenal incendentaloma, and thus is typically diagnosed later in life between 40-60 years in age (Drougat et al. 2015). In individuals with Cushing syndrome, prolonged exposure to cortisol may lead to obesity, severe fatigue, weak muscles, high blood pressure, high blood sugar, irritability, and anxiety. In individuals with PMAH, adrenocortical nodules tend to be slow growing and cortisol dysregulation progresses more slowly (Assié et al. 2013). It is most often sporadic, although familial cases have been reported, often occurring bilaterally, but can also occur in unilaterally (Alencar et al. 2014). The disease may show decreased penetrance, and also variable expressivity, as some individuals in a family may be severely affected and others in the family may have subclinical manifestations (Assié et al. 2013). Treatment is often surgical, but in select cases receptor antagonists may be used (De Venanzi et al. 2014).


Primary macronodular adrenal hyperplasia is often sporadic, but can also be inherited in an autosomal dominant manner. Inherited forms are caused by pathogenic variants in the ARMC5 gene, which is thought to encode a tumor suppressor as a two-hit model has been observed in affected tissues (Assié et al. 2013). Reported pathogenic variants include missense, nonsense, splicing mutations, and small insertions and deletions (Correa et al. 2015; Alencar et al. 2014). One gross deletion of the whole gene has been reported (Assié et al. 2013).

Testing Strategy

The armadillo repeat-containing protein 5 is encoded by 6 exons (1-6) from the ARMC5 gene on chromosome 16p11.2. Testing is accomplished by amplifying each coding exon and ~20 bp of adjacent noncoding sequence, then determining the nucleotide sequence using standard Sanger dideoxy sequencing methods and a capillary electrophoresis instrument. We will also sequence any single exon (Test #100) in family members of patients with a known mutation or to confirm research results.

Indications for Test

Individuals with a clinical presentation of primary macronodular adrenal hyperplasia and individuals with a family history.


Official Gene Symbol OMIM ID
ARMC5 615549
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Primary Macronodular Adrenal Hyperplasia 615954

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Genetic Counselors
  • Alencar G.A. et al. 2014. The Journal of Clinical Endocrinology and Metabolism. 99: E1501-9. PubMed ID: 24708098
  • Assié G. et al. 2013. The New England Journal of Medicine. 369: 2105-14. PubMed ID: 24283224
  • Correa R. et al. 2015. European Journal of Endocrinology / European Federation of Endocrine Societies. 173: 435-40. PubMed ID: 26162405
  • De Venanzi A. et al. 2014. Current Opinion in Endocrinology, Diabetes, and Obesity. 21: 177-84. PubMed ID: 24739311
  • Drougat L. et al. 2015. European Journal of Endocrinology / European Federation of Endocrine Societies. 173: M121-31. PubMed ID: 26264719
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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.

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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.
  • 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.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -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 ml -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 stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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