CALR Mutation
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The CALR mutation test is performed on a blood or bone marrow sample to look for mutations in the CALR gene. It is used to help diagnose certain myeloproliferative neoplasms, particularly essential thrombocythaemia and primary myelofibrosis.
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 full blood count (FBC) and your healthcare professional suspects that you may have a bone marrow disorder, especially essential thrombocythaemia (ET) or primary myelofibrosis (PMF)
Sample required?
A blood sample taken from a vein in your arm or sometimes a sample of bone marrow
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 thrombocythaemia (ET)—there are too many platelet-producing cells (megakaryocytes) in the bone marrow
- Primary myelofibrosis (PMF), also known as chronic idiopathic myelofibrosis—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 thrombocythaemia 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 paediatric 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.
How is the sample collected for testing?
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.
Is any test preparation needed to ensure the quality of the sample?
No test preparation is needed.
Common questions
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 thrombocythaemia (ET) and primary myelofibrosis (PMF).
Testing for genetic abnormalities associated with MPNs is generally done as follow-up if someone has a significantly increased haemoglobin, haematocrit, red blood cell and/or platelet count, or blood film 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.
The CALR mutation test may be requested, along with other tests, when a healthcare professional suspects that a person has a myeloproliferative neoplasm (MPN) such as essential thrombocythaemia (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 recognised as an MPN, often during routine testing. However, a healthcare professional may suspect an MPN and arrange testing when a person has abnormal results on a full blood count (FBC) 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 anaemia, such as fatigue and weakness
A positive CALR mutation test means that the person likely has a myeloproliferative neoplasm (MPN), specifically essential thrombocythaemia (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 thrombocythaemia and 25–30% of adults with primary myelofibrosis have a CALR mutation. The mutation is also rarely found in people with chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS), and chronic myeloid leukaemia (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 leukaemia (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 thrombocythaemia 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”).
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.
No, the CALR mutation associated with MPNs is somatic, meaning it is acquired during cell division and is not passed on to children.
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 to a reference laboratory (specialised testing laboratory) for analysis and interpretation.
Test results can take several days to two weeks to arrive.
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 thrombocythaemia (ET) and primary myelofibrosis (PMF). In addition, mutations in the myeloproliferative leukaemia (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 leukaemia.