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Genotyping for 9p21 Single Nucleotide Polymorphisms to Predict Risk of Cardiovascular Disease or Aneurysm

Policy Number: MP-542

ARCHIVED – Refer to AIM Genetic Testing Guidelines Effective 3/1/20

Latest Review Date: September 2019

Category: Laboratory

Effective March 28, 2016: Active Policy but no longer scheduled for regular literature reviews and updates.


Genotyping for 9p21 single nucleotide polymorphisms is considered not medically necessary and investigational for all clinical uses including but not limited to identification patients who may be at risk for the following:

  • Cardiovascular disease or its manifestations (e.g., MI myocardial infarction, ischemic stroke, PAD peripheral arterial disease, coronary artery calcification), or
  • Aneurysmal disease (AAA abdominal aortic aneurysms, intracranial aneurysms, polypoidal choroidal vasculopathy)


A number of highly correlated single nucleotide polymorphisms (SNPs) found at the 9p21 locus have been significantly associated with risk of myocardial infarction (MI), particularly early onset MI, and other manifestations of cardiovascular disease (CVD). Associations between 9p21 SNPs and risk of abdominal aortic aneurysm (AAA), intracranial aneurysms, and other vascular disease have also been reported. Genotyping for 9p21 SNPs has been investigated to identify patients at risk of cardiovascular disorders.

Several laboratories offer 9p21 genotyping. For example, the Berkeley HeartLab (Quest Diagnostics) offers the 9p21 Genotype Test, which detects the rs10757278 A>G and rs1333049 G>C SNPs within the 9p21 locus of chromosome 9. Baylor Miraca Genetics Laboratories offers genotyping of the rs10757278 A>G polymorphism at 9p21.

Cardiac risk genotyping panels offered by other laboratories may include and individually report 9p21 SNP results. For example, the deCODE MI™ (deCODE Genetics, Reykjavik) test genotypes 9p21.3 rs10757278 in addition to seven other SNPs from other chromosomal loci to estimate the risk of CHD and MI.


This policy is based on literature review most recently performed September 27, 2019.

Summary of Evidence

The association of single nucleotide polymorphisms at the 9p21 locus with coronary artery/heart disease (CAD/CHD) incidence and outcomes (clinical validity) is well-established and consistent in multiple independent populations, with evidence of increasing severity of outcomes with increasing risk allele dosage. The clinical validity for the association of 9p21 polymorphisms ischemic stroke, aneurysms, or other vascular disorders is less well-studied and less certain. Despite the evidence that 9p21 polymorphisms are associated with CAD/CHD outcomes, the clinical utility of 9p21 genotyping has not been established. Studies have conclusively demonstrated that 9p21 genotyping significantly improves risk reclassification after initial classification by traditional risk factors, or that addition of 9p21 genotyping to traditional risk factors improves risk assessment. No studies were identified that evaluate whether the use of 9p21 genotyping is associated with changes in patient management, improvements in clinical outcomes, or both. There is insufficient evidence to determine if the use of the 9p21 genetic variant predicts clinical events or improves health outcomes, thus, 9p21 genotyping for all applications is investigational.

Practice Guidelines And Position Statements

In 2013, the American College of Cardiology Foundation and the American Heart Association Task Force on Practice Guidelines issued guidelines on the assessment of cardiovascular risk, which did not address assessment of 9p21 polymorphisms.

The EGAPP Working Group published a recommendation on “genomic profiling to assess cardiovascular risk to improve cardiovascular health” which included a recommendation on 9p21 profiling alone based on Palomaki et al. In general, the EWG found “… insufficient evidence to recommend testing for the 9p21 genetic variant or 57 other variants in 28 genes . . . to assess risk for cardiovascular disease (CVD) in the general population, specifically heart disease and stroke. The EWG found that the magnitude of net health benefit from use of any of these tests alone or in combination is negligible. The EWG discourages clinical use unless further evidence supports improved clinical outcomes. Based on the available evidence, the overall certainty of net health benefit is deemed “low.”

U.S. Preventive Services Task Force Recommendations

No recommendations for 9p21 genotyping to identify risk for cardiovascular disease have been identified.


Genotyping, chromosome 9p21, cardiovascular disease risk, aneurysm, EarlyMICheck™ Genotype Test, deCODE MI™, CardioIQ®


There is no manufactured test kit for 9p21 genotyping that has been reviewed by the U.S. Food and Drug Administration (FDA). 9p21 genotyping tests are laboratory-developed tests (LTD), offered by clinical laboratories licensed under Clinical Laboratory Improvement Amendment (CLIA) for high-complexity testing.

The Berkeley HeartLab offers the 9p21 Genotype Test, which detects the rs10757278 A>G and rs1333049 G>C SNPs within the 9p21 locus of chromosome. The information on the website (available online at: indicates that the SNPs have been shown to predict increased risk for early onset MI, for abdominal aortic aneurysm, and for myocardial infarction / coronary heart disease in general. It is suggested that the test may help identify patients at increased risk for these conditions, alerting providers to characterize and reduce other contributing risk factors.

Cardiac risk genotyping panels offered by other laboratories may include and individually report 9p21 SNP results. For example, the deCODE MI™ (deCODe Genetics, Reykjavik) test genotypes 9p21.3 rs10757278 in addition to 7 other SNPs from other chromosomal loci to estimate the risk of coronary heart disease and MI.


Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.


CPT Codes:

There is no specific CPT code for this test. If the specific analyte is listed in codes 81161-81355 or 81400-81408, that CPT code would be reported along with the unlisted code 81479 for the analytes that are not listed.

If none of the analytes are listed in the more specific CPT codes, unlisted code 81479 would be reported for the whole test.

The Quest website reports that their Cardio IQ® 9p21 Genotype test is reported with code 81479


Unlisted molecular pathology procedure


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  50. Scheffold T, Kullmann S, Huge A et al. Six sequence variants on chromosome 9p21.3 are associated with a positive family history of myocardial infarction: a multicenter registry. BMC Cardiovasc Disord 2011; 11:9.
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Medical Policy Group, April 2011 (1): Update to Policy, Key Points, Key Words and References

Medical Policy Administration Committee, April 2011

Available for comment April 13 – May 30, 2011

Medical Policy Group, May 2011 (1): Update to Policy, Key Points and References

Medical Policy Administration Committee, June 2011

Available for comment June 8 – July 25, 2011

Medical Policy Group, May 2012 (1): Update to Key Points and References; no change to policy statement

Medical Policy Panel, April 2013

Medical Policy Group, April 2013 (1): Update to Descriptions, Key Points, Key Words and References; no change to policy statement, remains investigational; all corresponding tables and informational pages have been updated

Medical Policy Administration Committee, October 2013

Medical Policy Group, January 2014 (1): Creation of individual policy with all references related to 9p21 SNPs removed from medical policy #136; no change to policy statement

Medical Policy Panel, April 2014

Medical Policy Group, April 2014 (1): Update to Key Points and References; no change to policy statement

Medical Policy Panel, April 2015

Medical Policy Group, May 2015 (3): Updates to Description, Key Points, Current Coding, and References; policy statement verbiage updated to include myocardial infarction, no change to intent.

Medical Policy Panel, March 2016

Medical Policy Group, March 2016 (3): Update to Key Words only; no new information available; no change to policy statement; retiring policy

Medical Policy Group, September 2019 (9): Updated Description, Key Points, References. Removed outdated previous coding section. No change to policy statement.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.