Also Known As:
CALR Gene Mutation Exon 9

Formal Name:
Calreticulin Mutation Analysis (myeloproliferative neoplasm)

This article was last modified on February 19, 2020

Learn more about...

Complete Blood Count (CBC)

At a Glance

Why Get Tested?

To help diagnose bone marrow disorders known as myeloproliferative neoplasms (MPNs), in which the bone marrow produces too many of one or more types of blood cells

When To Get Tested?

When you have abnormal results on a complete blood count (CBC) and your health care practitioner suspects that you may have a bone marrow disorder, especially essential thrombocythemia (ET) or primary myelofibrosis (PMF)

Sample Required?

A blood sample is obtained by inserting a needle into a vein in the arm. Sometimes a bone marrow aspiration and biopsy may be done to collect a sample for testing.

Test Preparation Needed?

None

What is being tested?

The calreticulin gene, called CALR for short, is responsible for making a protein called calreticulin. The exact function of calreticulin protein remains largely unknown, but it is likely involved in ensuring the correct folding of new proteins, maintaining correct calcium levels in cells, and a number of other cell functions. Mutations of the CALR gene are associated with bone marrow neoplasms that cause the production of too many blood cells. These blood disorders are collectively known as myeloproliferative neoplasms (MPNs). The CALR mutation test looks for abnormalities in the CALR gene to help diagnose and classify MPNs.

The MPNs most commonly associated with CALR mutations are:

Essential thrombocythemia (ET)—there are too many platelet-producing cells (megakaryocytes) in the bone marrow
Primary myelofibrosis (PMF), also known as chronic idiopathic myelofibrosis or agnogenic myeloid metaplasia—there are too many platelet-producing cells and cells that produce scar tissue in the bone marrow

CALR mutations are the second most common genetic abnormality (after JAK2 mutations) associated with essential thrombocythemia or primary myelofibrosis. They are present in about 20-25% of adults with ET and 25-30% of adults with PMF. Although rare and not well understood in children, 50% of pediatric PMF patients had CALR mutations.

The CALR mutation is acquired after birth as opposed to inherited. It is caused by the addition or removal of small amounts of genetic material to a region of the gene called exon 9. This leads to an abnormal calreticulin protein. It is not yet understood how the mutant protein leads to signs and symptoms of MPN. While more than 50 types of CALR mutation have been found, only the two most common variants associated with MPNs are included in conventional PCR testing. Next generation sequencing (NGS)-based analysis should detect all mutation variants but is not widely available.

In addition to helping diagnose MPNs, CALR mutation testing can provide information about a person’s prognosis. Studies have shown that compared to individuals with the JAK2 mutation, those with the CALR mutation had a milder disease course, fewer signs and symptoms of blood clotting (thrombotic episodes), and better survival.

Common Questions

How is it used?

The CALR mutation test is used to help diagnose and classify bone marrow disorders that lead to the production of too many blood cells. These disorders are known as myeloproliferative neoplasms (MPNs).

CALR mutations are the second most common genetic abnormality associated with two types of MPNs: essential thrombocythemia (ET) and primary myelofibrosis (PMF).

Testing for genetic abnormalities associated with MPNs is generally done as follow-up if someone has a significantly increased hemoglobin, hematocrit, red blood cell and/or platelet count, or blood smear findings suggesting myelofibrosis, along with clinical signs and symptoms suggesting an MPN.

Testing for CALR mutation is usually done in conjunction with tests for other mutations associated with MPNs, such as BCR-ABL1 and JAK2 mutation tests.

When is it ordered?

The CALR mutation test may be ordered, along with other tests, when a healthcare practitioner suspects that a person has a myeloproliferative neoplasm (MPN) such as essential thrombocythemia (ET) or primary myelofibrosis (PMF). It is typically tested after someone suspected of having an MPN has tested negative for a mutation of the BCR-ABL1 and JAK2 genes.

Sometimes people with MPNs may have no symptoms or a few, relatively mild ones that may be present for years before being recognized as an MPN, often during a routine physical. However, a healthcare practitioner may suspect an MPN and order testing when a person has abnormal results on a complete blood count (CBC) in combination with several signs and symptoms, such as:

Enlarged spleen (splenomegaly) or liver (hepatomegaly), abdominal pain
Excessive clotting (e.g., a blood clot in a vein or artery)
Easy bruising or bleeding
Headache, dizziness, vision problems
Signs and symptoms related to anemia, such as fatigue and weakness

What does the test result mean?

A positive CALR mutation test means that the person likely has a myeloproliferative neoplasm (MPN), specifically essential thrombocythemia (ET) or primary myelofibrosis (PMF).

Other testing, such as a bone marrow biopsy, may need to be performed to determine which MPN the person has and to evaluate its severity.

About 20-25% of adults with essential thrombocythemia and 25-30% of adults with primary myelofibrosis have a CALR mutation. The mutation is also rarely found in people with chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myeloid leukemia (CML).

In 2016, the World Health Organization (WHO) revised its diagnostic criteria for MPNs. The presence of the CALR exon 9 mutation is one of three major criteria listed for diagnosis of ET and PMF.

Carrying a mutated CALR gene can have implications for an individual’s MPN prognosis and disease progress. Studies have found that people with CALR mutations have better overall survival than those with JAK2 or myeloproliferative leukemia (MPL) mutations. People with CALR mutations also have a lower risk of harmful blood clots (thrombosis) than those with JAK2-positive ET.

A negative result typically means that the CALR mutation being tested for was not detected. It is possible to have a negative result and still carry an uncommon CALR mutation that the test cannot detect. It is also possible, though unlikely, that the test failed to detect a CALR exon 9 mutation. Note that next generation sequencing (NGS)-based analysis should detect all mutation variants in the CALR gene, but the test is not widely available.

A negative result does not rule out the possibility of having an MPN. Ten to 15 percent of essential thrombocythemia and primary myelofibrosis cases have no common genetic abnormality associated with them, i.e., negative for JAK2, CALR and MPL mutations (known as “triple-negative MPN”).

Is there anything else I should know?

The discovery of genetic mutations underlying MPNs, beginning in 2005, represented a significant step forward in treating them. Drugs called targeted therapies designed to inhibit the abnormal proteins underlying the conditions show promise for being more effective than conventional MPN treatments. While targeted therapies have been developed to inhibit the JAK2 gene, CALR was discovered more recently and therapies to inhibit it are still being studied. Overall, developing targeted therapies to treat MPNs is a promising and active area of study.

Is the CALR mutation hereditary?

No, the CALR mutation associated with MPNs is somatic, meaning it is acquired during cell division and is not passed on to children.

Can this test be done in my health practitioner's office?

CALR mutation testing must be done in a laboratory that performs molecular testing. It is not offered by every laboratory and must often be sent out to a reference laboratory.

How long does it take for CALR mutation test results?

Test results can take several days to two weeks to arrive.

Are there other genetic mutations associated with MPNs?

Yes, JAK2 mutations are found in more than 95% of polycythemia vera (PV) cases. JAK2 mutations are also associated with 50-60% of cases of essential thrombocythemia (ET) and primary myelofibrosis (PMF). In addition, mutations in the myeloproliferative leukemia (MPL) gene are seen in a small percentage of adult ET and PMF patients, but not with PV. If someone carries the CALR mutation, that person will not carry JAK2 or MPL mutations, i.e., they are mutually exclusive. PV, ET and PMF are all rare in children and adolescents and although mutations might not be as common as in adults with these same diseases, not much is known. Genetic testing is also sometimes used to check for the presence or absence of a Philadelphia (Ph’) chromosome or a BCR-ABL1 translocation in a person suspected of having chronic myeloid leukemia.

View Sources

CALR mutation detection. Cleveland Clinic Laboratories. Available online at http://clevelandcliniclabs.com/wp-content/assets/pdfs/technical-briefs/calr-89979.pdf. Accessed March 2017.

Example patient report, CALR (calreticulin) exon 9 mutation analysis by PCR. ARUP Laboratories. Available online at http://ltd.aruplab.com/Tests/DownloadReport/2010673%2C%20Not%20Detected.pdf. Accessed March 2017.

Hematological malignancies, Thrombocytosis panel. Knight Diagnostic Laboratories. Available online at https://www.ohsu.edu/custom/knight-diagnostic-labs/home/test-details?id=Thrombocytosis+Panel. Accessed March 2017.

Nangalia, J. and Green, T. R. (2014 December 5). ASH Education Book. The evolving genomic landscape of myeloproliferative neoplasms. Available online at http://asheducationbook.hematologylibrary.org/content/2014/1/287.full. Accessed March 2017.

(© 1995-2017). CALR mutation analysis, myeloproliferative neoplasm (MPN). Mayo Medical Laboratories. Available online at http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/62912. Accessed March 2017.

Williams, M.E. (2014 January 7). CALR mutation in myeloproliferative diseases. NEJM Journal Watch. Available online at http://www.jwatch.org/na33026/2014/01/07/calr-mutation-myeloproliferative-disorders. Accessed March 2017.

(2014 January 7). NeoGenomics is the First Laboratory to Offer Calreticulin (CALR) Mutation Testing for the Diagnosis and Classification of Myeloproliferative Neoplasms. PR Newswire. Available online at http://www.prnewswire.com/news-releases/neogenomics-is-the-first-laboratory-to-offer-calreticulin-calr-mutation-testing-for-the-diagnosis-and-classification-of-myeloproliferative-neoplasms-239029251.html. Accessed March 2017.

Mehrotra, M. et al. (2015). Clinical validation of a multipurpose assay for detection and genotyping of CALR mutations in myeloproliferative neoplasms. American Journal of Clinical Pathology. Available online at http://www.medscape.com/viewarticle/855480_4. Accessed March 2017.

Gotlib, J. (2015 January 8). Mutation of the Calreticulin (CALR) Gene in Myeloproliferative Neoplasms. The Hematologist. Available online at http://www.hematology.org/Thehematologist/Years-Best/3546.aspx. Accessed March 2017.

Wu, Z. et al. (2015 February). Clinical relevance between CALR mutation and myeloproliferative neoplasms. Stem Cell Investigation. Available online at http://sci.amegroups.com/article/view/5719/6523. Accessed March 2017.

(2015 August). Myeloproliferative neoplasm: A diagnostic approach to peripheral blood evaluation. Mayo Clinic Mayo Medical Laboratories. Available online at http://www.mayomedicallaboratories.com/it-mmfiles/Myeloproliferative_Neoplasm_A_Diagnostic_Approach_to_Peripheral_Blood_Evaluation.pdf. Accessed March 2017.

Pietra, D. et al. (2015 November 17). Chronic myeloproliferative neoplasms, Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms. Leukemia. Available online at http://www.nature.com/leu/journal/v30/n2/full/leu2015277a.html. Accessed March 2017.

(2015 December 11). 2015 Blood Journal reports that CALR mutation reduced with Pegasys. MPN Research Foundation. Available online at http://www.mpnresearchfoundation.org/2015-Blood-Journal-Reports-that-CALR-Mutation-Reduced-with-Pegasys. Accessed March 2017.

Arber, D.A. et al. (2016). The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. Available online at http://www.bloodjournal.org/content/127/20/2391?sso-checked=true. Accessed March 2017.

(© 2016). CALR mutation analysis. University of Texas MD Anderson Cancer Center. Available online at https://www.mdanderson.org/research/research-resources/core-facilities/molecular-diagnostics-lab/services/calr-mutation-analysis.html. Accessed March 2017.

(March 7, 2107) Genetics Home Reference. What advances are being made in DNA sequencing? Available online at https://ghr.nlm.nih.gov/primer/genomicresearch/sequencing. March 2017.

Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017;129:667-679.

Rumi E, Cazzola M. Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms. Blood. 2017;129:680-692.

Ask a Laboratory Scientist

This form enables patients to ask specific questions about lab tests. Your questions will be answered by a laboratory scientist as part of a voluntary service provided by one of our partners, American Society for Clinical Laboratory Science. Please allow 2-3 business days for an email response from one of the volunteers on the Consumer Information Response Team.

CALR Mutation