National Medical Policy

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1 National Medical Policy Subject: Policy Number: Genetic Testing for Long QT Syndrome NMP490 Effective Date*: February 2005 Updated: August 2015 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate Medicaid Manuals for coverage guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link National Coverage Determination (NCD) National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* Other X None Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Genetic Testing for Long QT Syndrome Aug 15 1

2 Current Policy Statement Health Net, Inc. considers genetic testing for long QT (LQTS) syndrome medically necessary when any of the following are met: 1. The patient has been confirmed to have prolonged QT interval documented on electrocardiogram (ECG or EKG) and Holter monitor and acquired causes have been ruled out (e.g., drugs); or 2. There is a positive family history of sudden death in an individual of < 30 years of age and a genetic syndrome is suspected; or 3. There is a positive genetic test in a first-degree relative*. * Note: A first-degree relative is defined as the individual s parents, full siblings and children. Note: Health Net Inc. does not consider population screening for LQTS by DNA testing in all children, young athletes, or all young persons with unexplained syncope because neither the sensitivity nor specificity is such to make this testing meaningful. Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures will be replaced by ICD-10 code sets. Health Net National Medical Policies will now include the preliminary ICD-10 codes in preparation for this transition. Please note that these may not be the final versions of the codes and that will not be accepted for billing or payment purposes until the October 1, 2015 implementation date. ICD-9 Codes Long QT syndrome Paroxysmal ventricular tachycardia Ventricular fibrillation Ventricular flutter Cardiac arrest Syncope and collapse Nonspecific abnormal electrocardiogram (ecg) (ekg) Abnormal electrocardiogram (long QT syndrome) ICD-10 Codes Genetic Testing for Long QT Syndrome Aug 15 2

3 I45.81-I46.2 Long QT syndrome I47.0 Cardiac arrest I47.9 Paroxysmal tachycardia I49.o-I49.9 Other cardiac arrythmias R55 Syncope and collapse R94.30-R94.39 Abnormal results of cardiovascular function tests CPT Codes Long QT syndrome Gene analyses (e.g., KCNQ1, KCNH2, SCN5A, KCNE1. KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, SNTA1 and ANK2); full sequence analysis Long QT syndrome Gene analyses (e.g., KCNQ1, KCNH2, SCN5A, KCNE1. KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, SNTA1 and ANK2); known familial variant Long QT syndrome Gene analyses (e.g., KCNQ1, KCNH2, SCN5A, KCNE1. KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, SNTA1 and ANK2); duplication/deletion variants HCPCS Codes S3860 S3862 Genetic testing, comprehensive cardiac ion channel analysis, for variants in 5 major cardiac ion channel genes for individuals with high index of suspicion for familial Long QT Syndrome (LQTS) or related syndromes (Code deleted in 2013) Genetic testing, family-specific ion channel analysis, for blood-relatives of individuals (index case) who have previously tested positive for a genetic variant of a cardiac ion channel syndrome using either one of the above test configurations or confirmed results from another laboratory (Code deleted in 2013) Scientific Rationale Update August 2013 Lieve et al. (2012) completed a study with the goal to examine the diagnostic yield of genetic testing in 855 consecutive unrelated cases referred for Long QT syndrome (LQTS). Results: Eight hundred fifty five consecutive patients with a mean age at testing of 27.5±18.6 years, were referred for LQTS genetic testing and had accompanying clinical information. KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, CACNA1C, KCNJ2, CAV3, and SCN4B were analyzed using Next-Generation sequencing in all patients, and 395 patients were also tested for an additional two genes, AKAP9 and SNTA1. We retrospectively analyzed the diagnostic yield of this genetic test and factors that predicted the likelihood of a disease causing mutation using ANOVA, χ2, t-test, and receiver operator curves. At least one mutation was identified in 30.3% of the patients (n=259), and 18 patients (2.1%) had two mutations. Patients with two mutations had a longer QTc interval (p<0.01) than patients with one mutation. A longer QTc duration and family history of LQTS were each associated with a higher yield of positive results on genetic testing (p<0.01 for each). Using a QTc cutoff of 476msec or greater, the genetic testing had a sensitivity of 72% and a specificity of 49%. Mutations within the transmembrane domain of KCNQ1 were associated with a greater risk of cardiac arrest and syncope relative to mutations in other domains of the gene. Mutations in SCN5A were associated with a higher frequency of cardiac arrest (52.6%). Sequencing-based genetic testing has a sensitivity of 72% and has clinical utility. Genetic Testing for Long QT Syndrome Aug 15 3

4 Scientific Rationale Update November 2010 Identifying persons at risk for sudden cardiac death (SCD) continues to be challenging. The long QT syndrome (LQTS) is a genetic disorder characterized by prolongation of the QT interval in the electrocardiogram (ECG) and a propensity to "torsades de pointes" ventricular tachycardia frequently leading to syncope, cardiac arrest, or sudden death usually in young otherwise healthy individuals. The diagnosis of the long QT syndrome can be made by the electrocardiogram (ECG) in about 50% of cases. Genetic testing plays an important role and is particularly useful in cases with nondiagnostic or borderline ECG findings. The definitive diagnosis of LQTS is made on the basis of prolonged QT interval on the ECG or identification of a mutation in KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, or ANK2 genes, which encode cardiac ion channels. When a disease associated mutation is identified, molecular diagnosis can be important in guiding therapy, in family testing and in determining the cause of sudden cardiac death. Hofman et al (2010) investigated the follow-up and treatment of the mutationcarrying relatives of a proband with an inherited arrhythmia syndrome. After establishing the disease-causing deoxyribonucleic acid (DNA) mutation in probands, the investigators actively conducted cascade screening to identify, most often asymptomatic, relatives who are also at risk of life-threatening arrhythmias. They retrospectively collected data from their cardiogenetics database and patient records and analyzed whether the identified carriers received prophylactic treatment. 130 probands with a disease-causing mutation in one of the involved genes were identified, and 509 relatives tested positive for the disease-causing familial mutation. These subjects subsequently underwent cardiologic investigation (electrocardiography, exercise testing, Holter monitoring, ajmaline testing, echocardiography, where appropriate). After a mean follow-up of 69 +/- 31 months (LQTS), 60 +/- 19 months (CPVT), and 56 +/- 21 months (BrS), treatment was initiated and ongoing in 65% (199 of 308), 71% (85 of 120), and 6% (5 of 81) of the relatives in the LQTS, CPVT, and BrS families, respectively. Eight carriers were lost to follow-up. Treatment included drug treatment (n = 249) or implantation of pacemakers (n = 26) or cardioverter-defibrillators (n = 14). All mutation carriers received lifestyle instructions and a list of drugs to be avoided. The investigator concluded cascade screening in families with LQTS, BrS, or CPVT, which was based on DNA mutation carrying and subsequent cardiologic investigation, resulted in immediate prophylactic treatment in a substantial proportion of carriers, although these proportions varied significantly between the different diseases. Kapplinger et al (2009) performed a retrospective analysis of the first 2,500 cases (1,515 female patients, average age at testing 23 +/- 17 years, range 0 to 90 years) scanned for mutations in 5 of the LQTS-susceptibility genes: KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6). Overall, 903 referral cases (36%) hosted a possible LQTS-causing mutation that was absent in >2,600 reference alleles; 821 (91%) of the mutation-positive cases had single genotypes, whereas the remaining 82 patients (9%) had >1 mutation in > 1 gene, including 52 cases that were compound heterozygous with mutations in >1 gene. Of the 562 distinct mutations, 394 (70%) were missense, 428 (76%) were seen once, and 336 (60%) are novel, including 92 of 199 in KCNQ1, 159 of 226 in KCNH2, and 70 of 110 in SCN5A. The author concluded this cohort increases the publicly available compendium of putative LQTS-associated mutations by >50%, and approximately one-third of the most recently detected mutations continue to be novel. Although control population data suggest that the great majority of these mutations are Genetic Testing for Long QT Syndrome Aug 15 4

5 pathogenic, expert interpretation of genetic test results will remain critical for effective clinical use of LQTS genetic test results. Krahn et al (2009) investigated patients with apparently unexplained cardiac arrest and no evident cardiac disease (normal cardiac function on echocardiogram, no evidence of coronary artery disease, and a normal ECG). Sixty-three patients in 9 centers underwent systematic evaluation that included cardiac magnetic resonance imaging, signal-averaged ECG, exercise testing, drug challenge, and selective electrophysiological testing. Diagnostic criteria were based on accepted criteria or provocation of the characteristic clinical features for long-qt syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, early repolarization, arrhythmogenic right ventricular cardiomyopathy, coronary spasm, and myocarditis. A diagnosis was obtained in 35 patients (56%): Long-QT syndrome in 8, catecholaminergic polymorphic ventricular tachycardia in 8, arrhythmogenic right ventricular cardiomyopathy in 6, early repolarization in 5, coronary spasm in 4, Brugada syndrome in 3, and myocarditis in 1. Targeted genetic testing demonstrated evidence of causative mutations in 9 (47%) of 19 patients. Screening of 64 family members of these patients identified 15 affected individuals who were treated (24%). The remaining 28 patients (44%) were considered to have idiopathic ventricular fibrillation. The authors concluded systematic clinical testing, including drug provocation and advanced imaging, results in unmasking of the cause of apparently unexplained cardiac arrest in >50% of patients. This approach assists in directing genetic testing to diagnose genetically mediated arrhythmia syndromes, which results in successful family screening. Scientific Rationale The estimated prevalence of long QT syndrome (LQTS), or Romano-Ward syndrome, is 1:7000. In the United States, it may cause sudden death in 3,000 to 4,000 children and young adults each year. It results from serious structural defects in the person's cardiac potassium channels that do not allow proper transmission of the electrical impulses throughout the heart. It is characterized by QT prolongation and T wave abnormalities on the ECG, which are associated with tachyarrhythmias, including the ventricular tachycardia torsade de pointes (TdP), which may degenerate into ventricular fibrillation. In teenagers and young adults, TdP is usually self terminating, thus causing only a syncopal event, the most common symptom encountered. The syncope is typically precipitous and without warning, thus differing from the common vasovagal and orthostatic forms of syncope in which presyncope and other warning symptoms occur. Absence of aura, incontinence, and postictal findings help differentiate LQTS from seizures. The number of syncopal events in symptomatic individuals ranges from one to hundreds. In some instances, TdP degenerates to ventricular fibrillation and causes aborted cardiac arrest (if the patient is defibrillated) or sudden death. Stressors ranging from exercise to sudden emotion to loud sounds can trigger such events. Between a third and a half of gene carriers never have symptoms. Approximately 4-5% of gene carriers experience sudden death. People with LQTS may not have any symptoms. A family history or personal history of syncope, aborted cardiac arrest, or sudden death may lead to suspicion of LQTS. The diagnosis of the long QT syndrome can be made by the electrocardiogram (ECG) in about 50% of cases. However, in about 10% of cases, the QT interval on the initial ECG looks normal and in another 40% the QT interval is not sufficiently prolonged to permit a clear-cut diagnosis. The definitive diagnosis of LQTS is made on the basis of Genetic Testing for Long QT Syndrome Aug 15 5

6 prolonged QT interval on the ECG or identification of a mutation in KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, or ANK2 genes, which encode cardiac ion channels. The mutations responsible for the long QT syndrome are inherited in an autosomal dominant manner, which means that the mutant gene is on a non-sex chromosome and that each child of an affected parent has a 1 in 2 (50%) chance of inheriting it. Sporadic cases occur but are uncommon. No mutation is found on genotyping in about 30% of clinically affected patients. Some of these patients may have mutations of undiscovered genes, and some cases may be due to limitations of the analysis techniques. There is tremendous variability of expression and reduced penetrance of the QT and the symptom phenotypes. Genotyping can be very important for the approximately 35% of gene carriers with normal to borderline QT intervals of seconds, since they are difficult to diagnose and to separate from the large percentage of normals with these same QT values. Importantly, recent evidence indicates these gene carriers with reduced penetrance of the QT have essentially the same risk of syncope and sudden death as LQTS patients as a whole. In them, a correct diagnosis allows life saving treatment to be instituted. This can be quite important in evaluating relatives of a known LQTS patient or an unexplained sudden death victim. Long-term management of LQTS aims to reduce the QT-interval duration and prevent tachyarrythmias, which may lead to sudden death. is focused on the prevention of syncope, cardiac arrest, and sudden death through the use of betablockers, avoidance of triggering events (e.g., competitive sports, amusement park rides, scary movies, and jumping into cold water). Assured availability of external defibrillators, and use of cardiac pacemakers and implantable cardioverterdefibrillators (ICD) when necessary. Beta-blockers can help to maintain a normal heart rhythm in 90% of cases. Review History February 11, 2005 February 2007 March 2007 February 2009 November 2010 September 2011 August 2012 August 2013 August 2014 August 2015 Medical Advisory Council Update no revisions Coding Updates Coding updates Update no revision Update no revision Update no revision. Code updates Update - no revision. Code updates. Update no revisions. Code updates Update no revisions. Code updates This policy is based on the following evidence-based guidelines: 1. Vincent GM. Role of DNA testing for diagnosis, management, and genetic screening in long QT syndrome, hypertrophic cardiomyopathy, and Marfan syndrome. Editorial Heart 86:12-4. Available at: 2. Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope. Eur. Heart J., August 1, 2001; 22(15): Available at: 3. C. Wren. Sudden death in children and adolescents. Heart 2002; 88(4): Accessed at: Genetic Testing for Long QT Syndrome Aug 15 6

7 4. Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA Guidelines for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices. Updated Available at: 5. Hayes GTE Report. Long QT Syndrome (Familion). Jun Update Mar Updated May Zipes DP, Camm AJ, Borggrefe M et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines. Am Coll Cardiol 2006 Sep 5; 48(5): e Available at: References Update August Pellicia A, Link MS. Risk of sudden cardiac death in athletes. UpToDate. November 17, Seslar SP, Zimetbaum PJ, Berul CI, et al. Clinical features of congenital long QT syndrome. UpToDate. December 4, Zimetbaum PJ, Josephson ME. Genetics of congenital and acquired long QT syndrome. UpToDate. July 3, Zimetbaum PJ, Seslar SP, Berul CI, et al. Prognosis and management of congenital long QT syndrome. UpToDate. November 7, References Update August Hocini M, Pison L, Proclemer A, et al. Diagnosis and management of patients with inherited arrhythmia syndromes in Europe: results of the European Heart Rhythm Association Survey. Europace Apr;16(4): Tester DJ, Ackerman MJ. Genetics of Long QT Syndrome. Methodist Debakey Cardiovasc J Jan;10(1): Yoshinaga M, Kucho Y, Sarantuya J, et al. Genetic characteristics of children and adolescents with long-qt syndrome diagnosed by school-based electrocardiographic screening programs. Circ Arrhythm Electrophysiol Feb;7(1): References Update August Amin, AS, Giudicessi, JR, Tijsen, AJ, et al. Variants in the 3' untranslated region of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner. Eur Heart J Mar;33(6): Barsheshet, A, Goldenberg, IJOU, et al. Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to beta-blocker therapy in type 1 long-qt syndrome. Circulation Apr 24;125(16): Costa J, Lopes, CM, Barsheshet, A, et al. Combined assessment of sex- and mutation-specific information for risk stratification in type 1 long QT syndrome. Heart Rhythm Jun;9(6): Crotti L, Tester DJ, White WM, et al. Long QT syndrome-associated mutations in intrauterine fetal death. JAMA Apr 10;309(14): doi: /jama Lieve KV, Williams L, Daly A, et al. Results of Genetic Testing in 855 Consecutive Unrelated Patients Referred for Long QT Syndrome in a Clinical Laboratory. Genet Test Mol Biomarkers Jul;17(7): doi: /gtmb Epub 2013 Apr 30. Genetic Testing for Long QT Syndrome Aug 15 7

8 6. Park, JK, Martin, LJ, Zhang, X, et al. Genetic variants in SCN5A promoter are associated with arrhythmia phenotype severity in patients with heterozygous loss-of-function mutation. Heart Rhythm Jul;9(7): Refsgaard, L, Holst, AG, Sadjadieh, G, et al. High prevalence of genetic variants previously associated with LQT syndrome in new exome data. Eur J Hum Genet Aug;20(8): References Update August Barsheshet A, Moss AJ, McNitt S, et al. Risk of syncope in family members who are genotype-negative for a family-associated long-qt syndrome mutation. Circ Cardiovasc Genet Oct;4(5): Beckmann BM, Pfeufer A, Kääb S. Inherited cardiac arrhythmias: diagnosis, treatment, and prevention. Dtsch Arztebl Int Sep;108(37): Ingles J, Yeates L, O'Brien L, et al. Genetic testing for inherited heart diseases: longitudinal impact on health-related quality of life. Genet Med May Ingles J, Zodgekar PR, Yeates L, et al. Guidelines for genetic testing of inherited cardiac disorders. Heart Lung Circ Nov;20(11): References Update September Jiménez-Jáimez J, Tercedor-Sánchez L, Alvarez-López M, et al. Genetic testing of patients with long QT syndrome. Genetic testing of patients with long QT syndrome. Rev Esp Cardiol Jan;64(1): Shkol'nikova MA, Kharlap MS, Il'darova RA, et al. Genetic testing of patients with long QT syndrome. Rev Esp Cardiol Jan;64(1):71-4. References Update November Bai R, Napolitano C, Bloise R, et al. Yield of genetic screening in inherited cardiac channelopathies: how to prioritize access to genetic testing. Circ Arrhythm Electrophysiol Feb;2(1): Bokil NJ, Baisden JM, Radford DJ, Summers KM. Molecular genetics of long QT syndrome. Mol Genet Metab Sep;101(1): Hofman N, Tan HL, Alders M, et al. Active cascade screening in primary inherited arrhythmia syndromes: does it lead to prophylactic treatment? J Am Coll Cardiol Jun 8;55(23): Iturralde-Torres P, Medeiros-Domingo A. Genetics in long QT syndromes. Arch Cardiol Mex Dec;79 Suppl 2: Kapplinger JD, Tester DJ, Salisbury BA, et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm Sep;6(9): Kaufman ES. Mechanisms and clinical management of inherited channelopathies: long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome. Heart Rhythm Aug;6(8 Suppl):S Krahn AD, Healey JS, Chauhan V, et al. Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors With Preserved Ejection Fraction Registry (CASPER). Circulation Jul 28;120(4): ` Epub 8. Tester DJ, Benton AJ, Train L, et al. Prevalence and spectrum of large deletions or duplications in the major long QT syndrome-susceptibility genes and implications for long QT syndrome genetic testing. Am J Cardiol Oct 15;106(8): Genetic Testing for Long QT Syndrome Aug 15 8

9 References 1. Abriel H, Schlapfer J, Keller DI, et al. Molecular and clinical determinants of druginduced long QT syndrome: an iatrogenic channelopathy. Swiss Med Wkly Nov 27;134(47-48): Noda T, Shimizu W, Satomi K, et al. Classification and mechanism of Torsade de Pointes initiation in patients with congenital long QT syndrome. Eur Heart J Dec;25(23): Mancuso EM, Brady WJ, Harrigan RA, et al. Electrocardiographic manifestations: long QT Syndrome. J Emerg Med Nov;27(4): Leroy SS, Russell M. Long QT syndrome and other repolarization-related dysrhythmias. AACN Clin Issues Jul-Sep;15(3): Balaji S. Medical therapy for sudden death. Pediatr Clin North Am Oct;51(5): Towbin JA. Molecular genetic basis of sudden cardiac death. Pediatr Clin North Am Oct;51(5): Morillo CA, Baranchuk A. Current Management of Syncope: Treatment Alternatives. Curr Treat Options Cardiovasc Med Oct;6(5): Chiang CE. Congenital and acquired long QT syndrome; current concepts and management. Cardiology Review Jul;12(4): Cleveland Clinic Heart Center. Long QT syndrome (LQTS). 10. Khan IA. Long QT syndrome: diagnosis and management. American Heart Journal Jan;143(1): Tester DJ, McCormack J, Ackerman MJ. Prenatal molecular genetic diagnosis of congenital syndrome by strategic genotyping. The American Journal of Cardiology Mar;93(6): Moss A. Long QT syndrome. JAMA Apr;289(16): Vincent GM. Role of DNA testing for diagnosis, management, and genetic screening in long QT syndrome, hypertrophic cardiomyopathy, and Marfan syndrome. Heart. 2001;86(12): Menendez T, Achenbach S, Beinder E, Hofbeck M, Schmid O, Singer H, et al. Prenatal diagnosis of QT prolongation by magnetocardiography. Pacing and Clinical Electrophysiology Aug;23(8): Vincent GM, Timothy K, Fox J, Zhang L. The inherited long QT syndrome: from ion channel to bedside. Cardiology in Review Jan;7(1): Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Robinson JL, Priori SG, et al. Influence of genotype on the clinical course of the long-qt syndrome. International Long-QT Syndrome Registry Research Group. New Engl J Med Oct;339(14): Towbin JA. Molecular genetic aspects of the Romano-Ward long QT syndrome. Molecular and Cellular Cardiology Nov;21: Algra A, Tijssen JG, Roelandt JR, Pool J, Luben J. QTc prolongation measured by standard 12-lead electrocardiography is an independent risk factor for sudden death due to cardiac arrest. Circulation Jun;83(6): Important Notice General Purpose. Health Net's National Medical Policies (the "Policies") are developed to assist Health Net in administering plan benefits and determining whether a particular procedure, drug, service or supply is medically necessary. The Policies are based upon a review of the available clinical information including clinical outcome studies in the peer-reviewed published medical literature, regulatory status of the drug or device, evidence-based guidelines of governmental bodies, and evidence-based guidelines and positions of select national health professional organizations. Coverage determinations are made on a case-by-case basis and are subject to all of the terms, conditions, limitations, and exclusions of the member's contract, including medical necessity requirements. Health Net may use the Policies to determine whether under the Genetic Testing for Long QT Syndrome Aug 15 9

10 facts and circumstances of a particular case, the proposed procedure, drug, service or supply is medically necessary. The conclusion that a procedure, drug, service or supply is medically necessary does not constitute coverage. The member's contract defines which procedure, drug, service or supply is covered, excluded, limited, or subject to dollar caps. The policy provides for clearly written, reasonable and current criteria that have been approved by Health Net s National Medical Advisory Council (MAC). The clinical criteria and medical policies provide guidelines for determining the medical necessity criteria for specific procedures, equipment, and services. In order to be eligible, all services must be medically necessary and otherwise defined in the member's benefits contract as described this "Important Notice" disclaimer. In all cases, final benefit determinations are based on the applicable contract language. To the extent there are any conflicts between medical policy guidelines and applicable contract language, the contract language prevails. Medical policy is not intended to override the policy that defines the member s benefits, nor is it intended to dictate to providers how to practice medicine. Policy Effective Date and Defined Terms. The date of posting is not the effective date of the Policy. The Policy is effective as of the date determined by Health Net. All policies are subject to applicable legal and regulatory mandates and requirements for prior notification. If there is a discrepancy between the policy effective date and legal mandates and regulatory requirements, the requirements of law and regulation shall govern. * In some states, prior notice or posting on the website is required before a policy is deemed effective. For information regarding the effective dates of Policies, contact your provider representative. The Policies do not include definitions. All terms are defined by Health Net. For information regarding the definitions of terms used in the Policies, contact your provider representative. Policy Amendment without Notice. Health Net reserves the right to amend the Policies without notice to providers or Members. In some states, prior notice or website posting is required before an amendment is deemed effective. No Medical Advice. The Policies do not constitute medical advice. Health Net does not provide or recommend treatment to members. Members should consult with their treating physician in connection with diagnosis and treatment decisions. No Authorization or Guarantee of Coverage. The Policies do not constitute authorization or guarantee of coverage of particular procedure, drug, service or supply. Members and providers should refer to the Member contract to determine if exclusions, limitations, and dollar caps apply to a particular procedure, drug, service or supply. Policy Limitation: Member s Contract Controls Coverage Determinations. Statutory Notice to Members: The materials provided to you are guidelines used by this plan to authorize, modify, or deny care for persons with similar illnesses or conditions. Specific care and treatment may vary depending on individual need and the benefits covered under your contract. The determination of coverage for a particular procedure, drug, service or supply is not based upon the Policies, but rather is subject to the facts of the individual clinical case, terms and conditions of the member s contract, and requirements of applicable laws and regulations. The contract language contains specific terms and conditions, including pre-existing conditions, limitations, exclusions, benefit maximums, eligibility, and other relevant terms and conditions of coverage. In the event the Member s contract (also known as the benefit contract, coverage document, or evidence of coverage) conflicts with the Policies, the Member s contract shall govern. The Policies do not replace or amend the Member s contract. Policy Limitation: Legal and Regulatory Mandates and Requirements The determinations of coverage for a particular procedure, drug, service or supply is subject to applicable legal and regulatory mandates and requirements. If there is a discrepancy between the Policies and legal mandates and regulatory requirements, the requirements of law and regulation shall govern. Reconstructive Surgery CA Health and Safety Code requires health care service plans to cover reconstructive surgery. Reconstructive surgery means surgery performed to correct or repair abnormal structures of the body caused by congenital defects, developmental abnormalities, trauma, infection, tumors, or disease to do either of the following: (1) To improve function or (2) To create a normal appearance, to the extent possible. Reconstructive surgery does not mean cosmetic surgery," which is surgery performed to alter or reshape normal structures of the body in order to improve appearance. Genetic Testing for Long QT Syndrome Aug 15 10

11 Requests for reconstructive surgery may be denied, if the proposed procedure offers only a minimal improvement in the appearance of the enrollee, in accordance with the standard of care as practiced by physicians specializing in reconstructive surgery. Reconstructive Surgery after Mastectomy California Health and Safety Code requires treatment for breast cancer to cover prosthetic devices or reconstructive surgery to restore and achieve symmetry for the patient incident to a mastectomy. Coverage for prosthetic devices and reconstructive surgery shall be subject to the co-payment, or deductible and coinsurance conditions, that are applicable to the mastectomy and all other terms and conditions applicable to other benefits. "Mastectomy" means the removal of all or part of the breast for medically necessary reasons, as determined by a licensed physician and surgeon. Policy Limitations: Medicare and Medicaid Policies specifically developed to assist Health Net in administering Medicare or Medicaid plan benefits and determining coverage for a particular procedure, drug, service or supply for Medicare or Medicaid members shall not be construed to apply to any other Health Net plans and members. The Policies shall not be interpreted to limit the benefits afforded Medicare and Medicaid members by law and regulation. Genetic Testing for Long QT Syndrome Aug 15 11