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Familial Hypocalciuric Hypercalcemia (FHH) via the AP2S1 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
AP2S1 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8649AP2S181479 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


  • Angela Gruber, PhD

Clinical Features and Genetics

Clinical Features

Familial hypocalciuric hypercalcemia (FHH) is a heritable disorder of mineral homeostasis characterized by lifelong elevation of serum calcium concentrations. FHH patients are usually asymptomatic and the disorder is generally considered benign. Clinical features of FHH include hypermagnesemia and low urinary calcium excretion. FHH patients have normal or mildly elevated circulating parathyroid hormone (PTH) level. In uncommon symptomatic cases, some adult patients have chondrocalcinosis and pancreatitis while some children may develop neonatal severe hyperparathyroidism (NSHPT). The age of FHH onset is mostly in infancy, but severe FHH can present in either childhood or early adulthood. FHH is a genetically heterogeneous disorder and consists of three variants: FHH1, FHH2 and FHH3. FHH3 is caused by dominant AP2S1 mutations (Nesbit et al. 2013).


Familial hypocalciuric hypercalcemia type 3 (FHH3) is an autosomal dominant disorder caused by AP2S1 mutations (Nesbit et al. 2013). AP2S1 has 5 coding exons that encode the σ-2 subunit of the adaptor-related protein complex 2 (AP2), which is a central component of clathrin-coated vesicles (CCVs) pivotal in clathrin-mediated endocytosis. Pathogenic defects found to date in the AP2S1 gene are all missense substitutions only occurring at codon p.Arg15 (Nesbit et al. 2013; Hendy et al. 2014). The other two FHH-causative genes are CASR (FHH1) and GNA11 (FHH2) (Nesbit et al. 2013; Hannan et al. 2013). CASR mutations were detected in around 65% of FHH patients.

Clinical Sensitivity - Sequencing with CNV PGxome

Heterozygous AP2S1 missense mutations were found in 13% to 20% of unrelated FHH patients who were negative for CASR mutations (Nesbit et al. 2013; Hendy et al. 2014).

Testing Strategy

This test provides full coverage of all coding exons of the AP2S1 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

Candidates for this test are patients with familial hypocalciuric hypercalcemia. Testing is also indicated for family members of patients who have known AP2S1 mutations.


Official Gene Symbol OMIM ID
AP2S1 602242
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Hypocalciuric Hypercalcemia, Familial, Type III AD 600740

Related Tests

Familial Hypocalciuric Hypercalcemia (FHH) Panel
Hypoparathyroidism Panel


  • Hannan FM, Thakker RV. 2013. Calcium-sensing receptor (CaSR) mutations and disorders of calcium, electrolyte and water metabolism. Best Pract. Res. Clin. Endocrinol. Metab. 27: 359371. PubMed ID: 23856265
  • Hendy GN, Canaff L, Newfield RS, Tripto-Shkolnik L, Wong BYL, Lee BSP, Cole DEC. 2014. Codon Arg15 mutations of the AP2S1 gene: common occurrence in familial hypocalciuric hypercalcemia cases negative for calcium-sensing receptor (CASR) mutations. J. Clin. Endocrinol. Metab. 99: E13111315. PubMed ID: 24731014
  • Nesbit MA, Hannan FM, Howles SA, Babinsky VN, Head RA, Cranston T, Rust N, Hobbs MR, Heath H 3rd, Thakker RV. 2013. Mutations affecting G-protein subunit ?11 in hypercalcemia and hypocalcemia. N. Engl. J. Med. 368: 24762486. PubMed ID: 23802516
  • Nesbit MA, Hannan FM, Howles SA, Reed AAC, Cranston T, Thakker CE, Gregory L, Rimmer AJ, Rust N, Graham U, Morrison PJ, Hunter SJ, Whyte MP, McVean G, Buck D, Thakker RV. 2013. Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. Nat. Genet. 45: 9397. PubMed ID: 23222959


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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View Ordering Instructions

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2) Select Additional Test Options

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