Coverage Policy Manual
Policy #: 2013029
Category: Medicine
Initiated: August 2013
Last Review: March 2024
  Genetic Test: Hereditary Pancreatitis

Description:
In chronic pancreatitis (CP), recurrent attacks of acute pancreatitis evolve into a chronic inflammatory state with exocrine insufficiency, endocrine insufficiency manifested as diabetes, and increased risk for pancreatic cancer. Hereditary pancreatitis (HP) is a subset of CP defined clinically as a familial pattern of CP. Variants of several genes are associated with HP. Demonstration of a pathogenic variant in 1 or several of these genes can potentially be used to confirm the diagnosis of HP, provide information on prognosis and management, and/or determine the risk of CP in asymptomatic relatives of patients with HP.
 
Genetic Determinants
PRSS1 Variants
Whitcomb et al discovered that disease-associated variants of protease, serine, 1 (trypsin 1) (PRSS1) on chromosome 7q35 cause HP. PRSS1 encodes cationic trypsinogen. Gain of function variants of the PRSS1 gene cause HP by prematurely and excessively converting trypsinogen to trypsin, which then results in pancreatic autodigestion. Between 60% and 80% of people who have a PRSS1 variant will experience pancreatitis in their lifetimes; 30% to 40% will develop CP. Most, but not all, people with a disease-associated variant of PRSS1 will have inherited it from one of their parents. The proportion of HP caused by a de novo variant of PRSS1 is unknown. In families with 2 or more affected individuals in 2 or more generations, genetic testing has shown that most have a demonstrable disease-associated PRSS1 variant. In 60% to 100%, the variant is detected by sequencing technology (Sanger or next generation), and duplications of exons or the whole PRSS1 gene are seen in about 6%. Two PRSS1 point variants (p.Arg122His, p.Asn29Ile) are most common, accounting for 90% of mutations in affected individuals. Over 40 other PRSS1 sequence variants have been found, but their clinical significance is uncertain. Pathogenic PRSS1 mutations are present in 10% or less of individuals with CP (Whitcomb, 2004).
 
Targeted analysis of exons 2 and 3, where the common disease-associated variants are found, or PRSS1 sequencing, are first-line tests, followed by duplication analysis. The general indications for PRSS1 testing and emphasis on pre- and post-test genetic counseling have remained central features of reviews and guidelines (Fink, 2007; Solomon, 2012). However, several other genes have emerged as significant contributors to both HP and CP. These include cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene, serine peptidase inhibitor, Kazal type 1 (SPINK1) gene, chymotrypsin C (CTRC) gene, and claudin-2 (CLDN2) gene.
 
Autosomal recessive variants of CFTR cause CF, a chronic disease with onset in childhood that causes severe sinopulmonary disease and numerous gastrointestinal abnormalities. The signs and symptoms of CF can vary widely. On rare occasions, an affected individual may have mild pulmonary disease, pancreatic exocrine sufficiency, and may present with acute, recurrent acute, or CP (Solomon, 2012). Individuals with heterozygous mutations of the CFTR gene (CF carriers) have a 3- to 4-fold increased risk for CP. Individuals with 2 CFTR variants (homozygotes or compound heterozygotes) will benefit from CF-specific evaluations, therapies, and genetic counseling.
 
The SPINK gene encodes a protein that binds to trypsin and thereby inhibits its activity. Variants in SPINK are not associated with acute pancreatitis but are found, primarily as modifiers, in recurrent acute pancreatitis and seem to promote the development of CP, including for individuals with compound heterozygous mutations of the CFTR gene. Autosomal recessive familial pancreatitis may be caused by homozygous or compound heterozygous SPINK variants (Whitcomb, 2012).
 
The CTRC gene is important for the degradation of trypsin and trypsinogen, and 2 variants (p.R254W and p.K247_R254del) are associated with increased risk for idiopathic CP (odds ratio [OR]=4.6), alcoholic pancreatitis (OR=4.2), and tropical pancreatitis (OR=13.6) (Rosendahl, 2008). Tropical pancreatitis is a disease almost exclusively occurring in the setting of tropical climate and malnutrition.
 
The CLDN2 gene encodes a member of the claudin protein family, which acts as an integral membrane protein at tight junctions and has tissue-specific expression. Several single nucleotide variants in CLDN2 have been associated with CP.
 
Regulatory Status
Testing for variants associated with HP is typically done by direct sequence analysis or next-generation sequencing. A number of laboratories offer to test for the relevant genes, either individually or as panels.
 
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Genetic testing for HP is available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be certified by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
 
Coding
CPT code 81401 includes the following testing for hereditary pancreatitis:
 
PRSS1 (protease, serine, 1 [trypsin 1]) (e.g., hereditary pancreatitis), common variants (e.g., N29I, A16V,R122H)
 
CPT code 81404 includes the following testing for hereditary pancreatitis:
 
PRSS1 (protease, serine, 1 [trypsin 1]) (e.g., hereditary pancreatitis), full gene sequence
SPINK1 (serine peptidase inhibitor, Kazal type 1) (e.g., hereditary pancreatitis), full gene sequence
 
CPT code 81222 and/or 81223 might be reported for CFTR testing for hereditary pancreatitis:
 
81222: CFTR (cystic fibrosis transmembrane conductance regulator) (e.g., cystic fibrosis) gene analysis; duplication/deletion variants
81223: full gene sequence
 
Testing for duplication/deletion variants for PRSS1 and SPINK1 would be reported with the unlisted molecular pathology code 81479.

Policy/
Coverage:
Effective December 2014
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Genetic testing for PRSS1 and SPINK mutations to aid in the diagnosis of hereditary pancreatitis meets member benefit certificate primary coverage criteria for patients aged 18 years and younger with unexplained recurrent (>1 episode) acute or chronic pancreatitis with documented elevated amylase or lipase.
 
Genetic testing for CFTR mutations to aid in the diagnosis of hereditary pancreatitis meets member benefit certificate primary coverage criteria for patients aged 18 years and younger with unexplained recurrent (>1 episode) acute or chronic pancreatitis with documented elevated amylase or lipase if an abnormal sweat chloride test is documented.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Genetic testing for PRSS1, SPINK and CFTR mutations for hereditary pancreatitis in all other situations does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, genetic testing for PRSS1, SPINK and CFTR mutations for hereditary pancreatitis is considered investigational in all other situations. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Genetic testing for any other gene mutations for hereditary pancreatitis does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, genetic testing for any other gene mutations for hereditary pancreatitis is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to December 2014
 
Genetic testing for hereditary pancreatitis does not meet member benefit certificate primary coverage criteria that there be scientific evidence in improving health outcomes.
For members with contracts without primary coverage criteria, genetic testing for hereditary pancreatitis is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Investigational services are Plan exclusions.

Rationale:
Analytic Validity
Testing for mutations in the protease, serine, 1 (trypsin 1) (PRSS1), serine peptidase inhibitor (SPINK), and cystic fibrosis (CF) transmembrane conductance regulator (CFTR) genes is usually done by direct sequence analysis, which is the criterion standard for detecting a mutation that is present and/or excluding a mutation that is absent. Testing can also be done by next generation sequencing, which has an accuracy that approaches that of direct sequencing. In patients who test negative by either of these methods, duplication/deletion analysis may be performed to detect copy number variations. These genetic testing methods are considered to have high analytic validity.
 
Clinical Validity
The clinical validity of genetic testing for hereditary pancreatitis (HP) refers to the mutation detection rate in patients who have known HP.
 
There is a lack of published evidence on the percent of patients who are first identified as having clinically defined HP and then tested for genetic mutations. Most studies that examine the mutation detection rate use a population of patients with idiopathic chronic pancreatitis (CP) and do not necessarily require that patients have a family history of CP. In other studies, cohorts of patients with HP were defined by the presence of genetic mutations or family history, which therefore may include patients with genetic mutations who do not have a family history of CP.
 
A summary of the available studies are as follows:
 
Masson (2014)- 253 patients with idiopathic CP. Genes Tested: PRSS1, SPINK, CFTR, CTRC. Clinical Sensitivity: 23.7% “causal” mutation 60/253) 24.5% “contributory” mutation (62/253). Clinical Specificity was not reported.
Wang (2014): 75 children with idiopathic CP. Genes Tested: PRSS1, SPINK, CFTR, CTRC, CLDN2. Clinical Sensitivity: 66.7% (50/75) (with PRSS1 or SPINK mutations). Clinical Specificity was not reported.
Ceppa (2013): 87 patients with HP, defined by known genetic mutation or family history.  Genes Tested: PRSS1, SPINK, CFTR. Clinical Sensitivity 62% (54/87). Clinical Specificity was not reported.
Sultan (2012): 29 children with recurrent acute or CP. Genes Tested: PRSS1, SPINK, CFTR. Clinical Sensitivity 79% (23/29). Clinical Specificity was not reported.
Gasiorowska (2011): 14 patients with idiopathic CP, 46 control patients without pancreatitis. Genes Tested: PRSS1, SPINK. Clinical sensitivity 50% (7/14). Clinical specificity 11% (5/46).
Joergensen (2010): 122 patients with idiopathic pancreatitis. Genes Tested: PRSS1, SPINK, CFTR. Clinical sensitivity 40% (49/122). Clinical Specificity was not reported.
Rebours (2009): 200 patients with CP. Genes Tested: PRSS1. Clinical sensitivity 68% (136/200). Clinical Specificity was not reported.
Kelles (2006): 389 patients with recurrent or CP referred for genetic testing. Genes Tested: PRSS1, SPINK, CFTR. Clinical sensitivity 49% (185/381).  Clinical Specificity was not reported.
Truninger (2001): 104 patients with CP. Genes Tested: PRSS1. Clinical sensitivity 8% (8/1040).  Clinical Specificity was not reported.
Applebaum-Shapiro (2001): 115 patients with HP defined clinically; 349 unaffected family members. Genes Tested: PRSS1. Clinical sensitivity 52%(60/115). Clinical Specificity 13% (46/349).
 
These data on clinical validity demonstrate that genetic mutations are common in patients with CP. A very limited amount of evidence reports that genetic mutations are found in a small percentage of patients without pancreatitis. However, the true clinical sensitivity and specificity for genetic testing in cases of HP are uncertain for a number of reasons. First, the populations in these studies are defined differently, with most not consisting of patients with clinically defined HP. The populations are from different geographic regions, in which the prevalence of genetic mutations may vary. Some of the studies mix adult and pediatric populations, while others report on either adults or children. In the 2 studies that exclusively enrolled children, the rate of mutation detection was generally higher than other studies (67% and 79%). Finally, mutations tested for in these studies differ, with many studies not including all of the known genes that are associated with HP.
 
Other studies have reported on the rates of genetic mutations among populations of patients who were identified using less selective criteria, such as patients with isolated unexplained or recurrent acute pancreatitis or unexplained CP. Ballard et al reported results of a retrospective cohort study of 370 adults with unexplained pancreatitis, including recurrent acute pancreatitis, CP, or symptoms consistent with CP, who underwent pancreas-specific genetic testing at a single center (Ballard, 2015). Although 67 patients (18.1%) had any mutation detected, only 24 of these (6.4%) were found to have high-risk mutations, defined as (1) a single copy mutation of PRSS1, (2) homozygous mutations of CFTR, SPINK1, or CTRC, or (3) compound heterozygous mutations of CFTR, SPINK, and/or CTRC. High-risk mutations were more likely to be detected in patients who underwent complete gene sequencing methods compared with those who had targeted mutation testing methods. In a case-control study, Rai et el reported that SPINK1 mutations were found in 12.0% of 183 patients with acute pancreatitis, compared with 2.4% of 168 controls (p=0.006) (Rai, 2014). In a cohort study of 67 patients with acute recurrent pancreatitis of unknown etiology, Werlin et al reported that 34% of patients had a mutation in at least one gene associated with HP (Werlin, 2015).
 
The mutation detection rate for children with CP appears to be higher than for adults. Similarly, the proportion of patients with acute pancreatitis attributable to genetic causes is higher among younger patients. In a group of 309 subjects with acute pancreatitis, patients aged 35 and younger (n=66) were more likely to have a genetic cause of pancreatitis identified (10% vs 1.5%, p=0.003).23
 
Section Summary: Clinical Validity for Testing for Mutations Associated With HP
A number of studies report the mutation detection rate in various populations of patients with CP, but few studies enroll a population of patients with clinically defined HP. Therefore, the true clinical sensitivity and specificity cannot be determined. In studies that report on children, the detection rates are generally higher than other studies, suggesting that the mutation detection rate may be higher in children than in adults.
  
Clinical Utility
Potential types of clinical utility for PRSS1 genetic testing include confirmation of the diagnosis of HP, predictive testing in asymptomatic relatives, and prognostic testing to determine the course of the disease. In each case, demonstration of clinical utility depends on whether identification of a genetic defect leads to changes in medical and/or surgical management options, and whether these changes lead to improved health outcomes. Preconception (carrier) testing and prenatal (in utero) testing can also be performed, but are not addressed in this literature review.
 
Diagnostic Testing
There are no direct outcome data regarding the clinical utility of testing for confirmation of HP; that is, there are no studies that report outcome data in patients who have been tested for HP compared with patients who have not been tested.
 
Confirmatory testing can be performed in patients who experience acute pancreatitis that is otherwise unexplained, for recurrent acute pancreatitis of unclear cause, and/or for idiopathic CP. In all of these scenarios, a substantial percentage of patients will be found to have a genetic defect, thereby confirming the diagnosis of HP. Most treatments for the pain, maldigestion, and diabetes caused by HP are fundamentally the same as for other types of CP. Therefore, if a deleterious mutation associated with HP is found, treatment for CP is unlikely to change. Interventions for CP include a low-fat diet with multiple small meals, maintenance of good hydration, use of antioxidants, and avoidance of smoking and alcohol use. While all of these interventions may alter the natural history of the disease, there is no evidence that the impact differs for HP compared with other etiologies of CP.
 
Calcium channel blockers are currently being investigated as a potential treatment for HP. One small uncontrolled trial of amlodipine in 9 patients was identified in the literature (Morinville, 2007). This trial included patients 6 years or older who had CP and a known PRSS1 mutation. Treatment was continued for up to 11 weeks, and 4 patients successfully completed the full course of treatment. All 4 patients reported decreased symptoms, and 3 of the 4 patients had improved scores on the 36-Item Short-Form Health Survey outcome instrument. There were no differences before and after treatment in blood pressure, laboratory tests, or physical exam.
 
Total pancreatectomy with islet cell transplantation (or total pancreatectomy with islet autotransplantation [TP-IAT]) has been investigated in CP or recurrent acute pancreatitis, particularly as a treatment for intractable pain in patients with impaired quality of life in whom medical, endoscopic, or prior surgical treatment have failed. However, questions remain about the best timing of surgery, selection of candidates, evaluation of outcomes, and follow-up (Bellin, 2014). Chinnakotla et al conducted a retrospective study that compared outcomes after TP-IAT for patients with HP or familial pancreatitis compared with other causes of CP among 484 patients treated at a single institution from 1977 to 2012, 80 of whom had HP (Chinnakotla, 2014). Genetic testing was not available for all patients with suspected HP. Multiple causes of HP or familial pancreatitis were included: n=38 with PRSS1 mutations; n=9 with SPINK1 mutations; n=14 with CFTR mutations; and 19 with familial pancreatitis without a mutation specified. Patients with HP were younger at the time of TP-IAT (mean age, 21.9 years vs 37.9 years in nonhereditary CP, p<0.001), but had a longer history of pancreatitis (mean, 10.1 years vs 6.4 years in nonhereditary CP, p<0.001). Pain scores significantly improved after TP-IAT (p<0.001), with no significant differences between HP and nonhereditary CP.
 
Predictive Testing
Predictive testing can be performed in asymptomatic relatives of patients with known HP to determine the likelihood of CP. For this population, no direct evidence was identified that compared outcomes in patients tested for genetic mutations compared with patients not tested for genetic mutations. It is possible that at-risk relatives who are identified with genetic mutations may alter lifestyle factors such as diet, smoking and alcohol use, and this may delay the onset or prevent CP. However, evidence on this question is lacking, so that conclusions cannot be made on whether testing of asymptomatic family members of patients with HP improves outcomes.
 
Prognostic Testing
Several studies were identified that examined whether the severity and/or natural history of CP differs in patients with and without genetic mutations. A number of studies have reported that patients with HP have an earlier age of onset compared with patients with other etiologies of CP (Teich, 2008). Other studies have examined whether the severity and natural history differs for patients with HP, but these studies have not reported consistent findings. Some studies have reported that the progression of disease is slower in patients with  HP (Mullhaupt, 2005; Teich, 2008; Howes, 2004)  and that surgical intervention is required less often for patients with HP (Mullhaupt, 2005). However, 1 study also reported that the cumulative risk for exocrine failure was more than twice as high for patients with genetic mutations compared with patients without mutations (Howes, 2004). In another small study that compared the clinical course of patients with HP to those with alcoholic CP, most clinical manifestations were similar, but patients with HP had a higher rate of pseudocysts (Paolini, 1998).
 
Individuals with CP due to HP, like others with CP, are at increased risk for pancreatic cancer. In a survey of 246 patients with HP from 10 countries, the cumulative risk of pancreatic cancer by age 70 was estimated to be 40% (Lowenfels, 1997). In a series of 200 patients with HP from France, the cumulative incidence of pancreatic cancer at 50 years was 11% for men and 85% for women. At 75 years of age, the cumulative risk was 49% for men and 55% for women. There was no evidence identified that the risk of pancreatic cancer differs for patients with HP compared with patients with other forms of CP.
 
Screening for pancreatic cancer with computed tomography scanning, endoscopic ultrasound and/or endoscopic retrograde cholangiopancreatography has been recommended for patients with CP irrespective of etiology (Gemmel, 2009; Canto, 2008), but close surveillance has not yet been demonstrated to improve long-term survival for any of these methods in patients with CP.
 
Section Summary
The evidence on clinical utility does not support an improvement in health outcomes associated with genetic testing. For diagnostic testing, there is a lack of evidence that genetic testing leads to management changes. Several treatments for CP, including calcium channel blockers and TP-IAT, are under investigation; however, the evidence to date is insufficient to determine whether patients with HP respond differently to such treatments than other patients with CP. For prognostic testing, there have been some differences reported regarding the natural course of CP in patients with and without genetic mutations. The age of onset is consistently younger, and the progression of disease may be slower, but it is not possible to conclude whether the overall severity of disease or need for surgical intervention differs. The risk of pancreatic cancer is high for patients with HP, but no evidence was identified that establishes whether the risk of cancer is greater for patients with HP compared with other etiologies of CP. For testing asymptomatic, at-risk family members, there is a lack of evidence that genetic testing leads to interventions that delay or prevent the onset of pancreatitis.
 
Summary of Evidence
Numerous studies demonstrate that genetic mutations are found in a large percentage of patients with idiopathic chronic pancreatitis (CP). However, these studies are limited by wide variations in the patient populations and genes tested; as a result, it is not possible to determine the true prevalence of HP among patients with idiopathic CP, nor the sensitivity and specificity of genetic testing (clinical validity) in patients with a familial pattern of disease. The clinical utility of testing has not been demonstrated empirically.
 
While testing can confirm the diagnosis of hereditary pancreatitis (HP), there is no evidence that treatment is altered by testing or that health outcomes are improved. Similarly, predictive testing of at-risk relatives and prognostic testing have not been shown to improve outcomes. Predictive testing can better define the risk of developing CP, but there is no evidence that early interventions based on genetic testing alter the prevalence or course of disease. The prognosis of HP may differ from other etiologies of CP, but this evidence is mixed and there are no changes in management that result from refining the prognosis of CP. For children, recurrent acute or CP is a much less common event, making the yield of genetic testing higher. Expert opinion supports the use of genetic testing for HP in children, in spite of a lack of evidence for improvements in outcomes, due to the possibility of reduced diagnostic tests in the setting of a genetically-determined HP diagnosis.
 
Practice Guidelines and Position Statements
The American College of Medical Genetics issued a policy statement on laboratory standards and guidelines for population-based CF carrier screening in 2001, (Grody, 2001) which were updated in 2004 (Watson, 2004). These guidelines provide recommendations about specific mutation testing in CF, but do not specifically address genetic testing for suspected HP.
 
A 2001 European Consensus Conference developed guidelines for genetic testing of the PRSS1 gene, genetic counseling, and consent for genetic testing for HP (Ellis, 2001). The recommended indications for symptomatic patients included:
 
    • Recurrent (2 or more separate, documented episodes with hyperamylasemia) attacks of acute pancreatitis for which there is no explanation
    • Unexplained chronic pancreatitis
    • A family history of pancreatitis in a first- or second-degree relative
    • Unexplained pancreatitis in a child – if recurrent or requiring hospitalization
 
Predictive genetic testing, defined as genetic testing in an asymptomatic “at-risk” relative of an individual proven to have HP, was considered more complex. Candidates for predictive testing should be a first-degree relative of an individual with a well-defined HP gene mutation, capable of informed consent, and able to demonstrate an understanding of autosomal dominant inheritance, incomplete penetrance, variable expressivity, and the natural history of HP. Written informed consent must be documented before the genetic test is performed.
 
2018 Update
A literature search was conducted through November 2018.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
A systematic review and meta-analysis by Hu et al investigated the association between the p.R122H variant in the PRSS1 gene and the risk of CP (Hu, 2017). Eight case-control studies in which patients had CP, whether hereditary or of another cause were included. Analysis of all 8 reviewed studies (n=1733 patients with CP of all etiologies combined; n=2415 controls) showed an overall pooled odds ratio (OR) of 4.78 (95% confidence interval [CI], 1.13 to 20.20); heterogeneity was low (I 2 =32.2%). A subgroup analysis compared hereditary CP with nonhereditary CP in 4 studies (n=225 patients, n=2214 controls). There was low heterogeneity between the studies (p=0.235, I 2 =29.5%), with a pooled OR for an association between the p.R122H variant and the risk of hereditary CP of 65.52 (95% CI, 9.09 to 472.48). By comparison, the pooled OR for an association between the p.R122H variant, and an increased risk of nonhereditary CP was 2.79 (95% CI, 0.68 to 1.55).
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Weiss et al used genetic testing to analyze associations between common variants and acute pancreatitis (AP); 1462 patients with AP and 3999 healthy controls were evaluated (Weiss, 2018). For all AP patients, significant associations were found for PRSS1-PRSS2 variant (rs10273639) (OR 0.88, 95% CI: 0.81-0.97, p=0.01), RIPPLY variant (rs7057398) (OR 1.27, 95% CI: 1.07-1.5, p=0.005), and MORC4 (rs12688220) (OR 1.32, 95% CI: 1.12-1.56, p=0.001). Patients were included with AP of all etiologies and did not specifically have a history of recurrent episodes. The population was drawn from four European countries and the variant identification varied in the different populations. The results confirmed that PRSS1-PRSS2 is protective. The other two variants are being investigated for a pathogenic phenotype.
 
Zou et al analyzed 1196 controls and 1061 Han Chinese patients with idiopathic chronic pancreatitis (CP) tested with targeted next-generation sequencing of four CP-associated genes (SPINK1, PRSS1, CTRC, CFTR) (Zou, 2018).The objective of the study was to focus on rare variants defined as <1% frequency in the control population. Variants were identified in 535 (50.42%; OR=16.12; p<0.001) patients with CP compared to 71 (5.94%) controls. There was also an interest in assessing the influence of a variant on clinical presentation and disease onset. Median age at disease onset differed between mutation-positive (29.7±14.84 years) and mutation negative patients (43.01±15.97; p<0.001). When patients were divided into idiopathic (n=715), alcoholic (n=206), and smoking-associated (n=140) CP subgroups, the rates of pathogenic genotypes were 57.1%, 39.8%, and 32.1%, respectively. The study did not assess the variants more commonly encountered which are associated with a more defined phenotype.
 
 
PRACTICE GUIDELINES AND POSITION STATEMENTS
 
American College of Gastroenterology
The American College of Gastroenterology 2015 Clinical Guideline: Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes recommended genetic testing of patients with suspected familial pancreatic cancer to include analysis of BRCA1/2, CDKN2A, PALB2, and ATM. Evaluation for Peutz-Jeghers Syndrome, Lynch Syndrome, and hereditary pancreatitis-associated genes should be considered if personal and/or family history criteria are met for the syndrome (Syngal, 2015).
 
American Pancreatic Association
In 2014, the American Pancreatic Association published Practice Guidelines in Chronic Pancreatitis: Evidence-Based Report on Diagnostic Guidelines (Conwell, 2014). A classification guideline for the etiology of chronic pancreatitis includes genetic mutations in PRSS1, CFTR, SPINK1, and others.
 
 
International Consensus Guidelines for Chronic Pancreatitis
In 2018, the working group for the International Consensus Guidelines for Chronic Pancreatitis in collaboration with The International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society, PancreasFest Working Group, and the European Pancreatic Club, published consensus statements on the diagnosis and management of early chronic pancreatitis (Whitcomb, 2018). It included the following recommendation:
“Genetic variants are important risk factors for Early CP and can add specificity to the likely etiology, but they are neither necessary nor sufficient to make a diagnosis. (Quality assessment: moderate; Recommendation: strong; Agreement: strong)”
 
International Study Group of Pediatric Pancreatitis
The International Study Group of Pediatric Pancreatitis INSPPIRE (The International Study Group of Pediatric Pancreatitis: In search for a cuRE) consortium developed an expert consensus opinion on evaluation of children with acute recurrent and chronic pancreatitis (Gariepy, 2017). There was strong consensus that search for a genetic cause of ARP or CP should include PRSS1, SPINK1, CFTR and CTRC gene mutation testing.
 
American Society of Clinical Oncology
In 2018, the American Society of Clinical Oncology (ASCO) published “Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion” (Stoffel, 2018). ASCO reported that cancer-unaffected individuals should be offered genetic risk evaluation if they are: members of families with an identified pathogenic cancer susceptibility gene variant, from families that meet criteria for genetic evaluation for known hereditary syndromes that are linked to pancreatic cancer and, from families that meet criteria for familial pancreatic cancer. ASCO further considered what surveillance strategies should be used for individuals with predisposition to pancreatic ductal adenocarcinoma to screen for pancreatic and other cancers. Surveillance can be considered for individuals who are first-degree relatives of individuals with familial pancreatic cancer and/or individuals with a family history of pancreatic cancer who carry a pathogenic germline variant in genes associated with predisposition to pancreatic cancer.
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2020. No new literature was identified that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2020, a technical standard on CFTR variant testing by the ACMG was released (Deignan, 2020). The standard stated that indications for CFTR variant testing included diagnosis and carrier testing for individuals with idiopathic pancreatitis.
 
In 2018, the working group for the International Consensus Guidelines for Chronic Pancreatitis, in collaboration with the International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society, PancreasFest Working Group, and the European Pancreatic Club, published consensus statements on the diagnosis and management of early C There was an update to the guideline in 2020, and it included the following statement (Hegyi, 2020):
 
" In idiopathic disease, full sequence analysis of the CFTR, CPA1, CTRC, PRSS1 and SPINK1 gene exons and exon-intron boundaries and testing for the CEL gene pathogenic hybrid allele is recommended in order to explore the genetic background. (Quality assessment: low; Recommendation: conditional; Agreement: conditional)"
 
In 2021, the National Comprehensive Cancer Network (NCCN) released guidelines (version 1.2021) on genetic/familial high-risk assessment for breast, ovarian, and pancreatic cancers (NCCN, 2021). The NCCN recommends "germline testing for PRSS1, SPINK1, and other pancreatitis genes in individuals with a personal and/or family history of exocrine pancreatic cancer only if there is a personal and/or family history suggestive of hereditary pancreatitis"
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
HP is associated with a markedly increased risk of pancreatic cancer, although HP patients account for a small fraction of all cases of pancreatic cancer and are only a subset of the 10% of pancreatic cancers that are considered to have a genetic or familial predisposition. Individuals with HP have an estimated 40% to 55% lifetime risk of developing pancreatic cancer (Yadav, 2013).
 
It was found that the proportion of patients with AP attributable to genetic causes is higher among younger patients. In a group of 309 subjects with AP, patients ages 35 and younger (n=66) were more likely to have a genetic cause of pancreatitis identified (10%) than older patients (1.5%; p=.003) (Culetto, 2015).
 
A meta-analysis was conducted evaluating the association between loss-of-function CTRC variants (p.A73T,p.V235I, p.K247_R254del, and p.R254W) and CP (of various etiologies) (Takáts, 2022). Fourteen studies met inclusion criteria. All 4 variants were found more frequently in CP patients than controls: p.A73T (OR, 6.5; 95% CI, 2.4 to 17.8), p.V235I (OR, 4.5; 95% CI, 2.2 to9.1), p.K247_R254del (OR, 5.4; 95% CI, 2.6 to 11.0), and p.R254W (OR, 2.6; 95% CI, 1.6 to 4.2). The authors estimated that heterozygous loss-of-function CTRC variants increase the risk for CP approximately 3- to 7-fold.
 
In 2013, the American College of Gastroenterology (ACG) guidelines on management of acute pancreatitis included the following statement: “Genetic testing may be considered in young patients (<30 years old) if no cause [of acute pancreatitis] is evident, and a family history of pancreatic disease is present (conditional recommendation, low quality of evidence).”(Tenner, 2013).
 
The 2020 ACG guidelines for CP include the following recommendation for genetic testing in CP: "We recommend genetic testing in patients with clinical evidence of a pancreatitis-associated disorder or possible CP in which the etiology is unclear, especially in younger patients (strong recommendation, low quality of evidence)." (Gardner, 2020).
 
In 2014, the American Pancreatic Association published Practice Guidelines in Chronic Pancreatitis: Evidence-Based Report on Diagnostic Guidelines (Conwell, 2014). A classification guideline for the etiology of CP chronic pancreatitis (CP) includes genetic mutations inPRSS1, CFTR, SPINK1, and others.
 
In 2020, a technical standard on CFTR variant testing by the ACMG was released (Deignan, 2020). The standard stated that indications for CFTR variant testing included diagnosis and carrier testing for individuals with idiopathic pancreatitis.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2024. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
81220CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; common variants (eg, ACMG/ACOG guidelines)
81221CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; known familial variants
81222CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; duplication/deletion variants
81223CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; full gene sequence
81401Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) ABCC8 (ATP-binding cassette, sub-family C [CFTR/MRP], member 8) (eg, familial hyperinsulinism), common variants (eg, c.3898-9G&gt;A [c.3992-9G&gt;A], F1388del) ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) (eg, acquired imatinib resistance), T315I variant ACADM (acyl-CoA dehydrogenase, C-4 to C-12 straight chain, MCAD) (eg, medium chain acyl dehydrogenase deficiency), commons variants (eg, K304E, Y42H) ADRB2 (adrenergic beta-2 receptor surface) (eg, drug metabolism), common variants (eg, G16R, Q27E) APOB (apolipoprotein B) (eg, familial hypercholesterolemia type B), common variants (eg, R3500Q, R3500W) APOE (apolipoprotein E) (eg, hyperlipoproteinemia type III, cardiovascular disease, Alzheimer disease), common variants (eg, *2, *3, *4) CBFB/MYH11 (inv(16)) (eg, acute myeloid leukemia), qualitative, and quantitative, if performed CBS (cystathionine-beta-synthase) (eg, homocystinuria, cystathionine beta-synthase deficiency), common variants (eg, I278T, G307S) CFH/ARMS2 (complement factor H/age-related maculopathy susceptibility 2) (eg, macular degeneration), common variants (eg, Y402H [CFH], A69S [ARMS2]) DEK/NUP214 (t(6;9)) (eg, acute myeloid leukemia), translocation analysis, qualitative, and quantitative, if performed E2A/PBX1 (t(1;19)) (eg, acute lymphocytic leukemia), translocation analysis, qualitative, and quantitative, if performed EML4/ALK (inv(2)) (eg, non-small cell lung cancer), translocation or inversion analysis ETV6/RUNX1 (t(12;21)) (eg, acute lymphocytic leukemia), translocation analysis, qualitative, and quantitative, if performed EWSR1/ATF1 (t(12;22)) (eg, clear cell sarcoma), translocation analysis, qualitative, and quantitative, if performed EWSR1/ERG (t(21;22)) (eg, Ewing sarcoma/peripheral neuroectodermal tumor), translocation analysis, qualitative, and quantitative, if performed EWSR1/FLI1 (t(11;22)) (eg, Ewing sarcoma/peripheral neuroectodermal tumor), translocation analysis, qualitative, and quantitative, if performed EWSR1/WT1 (t(11;22)) (eg, desmoplastic small round cell tumor), translocation analysis, qualitative, and quantitative, if performed F11 (coagulation factor XI) (eg, coagulation disorder), common variants (eg, E117X [Type II], F283L [Type III], IVS14del14, and IVS14+1G&gt;A [Type I]) FGFR3 (fibroblast growth factor receptor 3) (eg, achondroplasia, hypochondroplasia), common variants (eg, 1138G&gt;A, 1138G&gt;C, 1620C&gt;A, 1620C&gt;G) FIP1L1/PDGFRA (del[4q12]) (eg, imatinib-sensitive chronic eosinophilic leukemia), qualitative, and quantitative, if performed FLG (filaggrin) (eg, ichthyosis vulgaris), common variants (eg, R501X, 2282del4, R2447X, S3247X, 3702delG) FOXO1/PAX3 (t(2;13)) (eg, alveolar rhabdomyosarcoma), translocation analysis, qualitative, and quantitative, if performed FOXO1/PAX7 (t(1;13)) (eg, alveolar rhabdomyosarcoma), translocation analysis, qualitative, and quantitative, if performed FUS/DDIT3 (t(12;16)) (eg, myxoid liposarcoma), translocation analysis, qualitative, and quantitative, if performed GALC (galactosylceramidase) (eg, Krabbe disease), common variants (eg, c.857G&gt;A, 30-kb deletion) GALT (galactose-1-phosphate uridylyltransferase) (eg, galactosemia), common variants (eg, Q188R, S135L, K285N, T138M, L195P, Y209C, IVS2-2A&gt;G, P171S, del5kb, N314D, L218L/N314D) H19 (imprinted maternally expressed transcript [non-protein coding]) (eg, Beckwith-Wiedemann syndrome), methylation analysis IGH@/BCL2 (t(14;18)) (eg, follicular lymphoma), translocation analysis; single breakpoint (eg, major breakpoint region [MBR] or minor cluster region [mcr]), qualitative or quantitative (When both MBR and mcr breakpoints are performed, use 81278) KCNQ1OT1 (KCNQ1 overlapping transcript 1 [non-protein coding]) (eg, Beckwith-Wiedemann syndrome), methylation analysis LINC00518 (long intergenic non-protein coding RNA 518) (eg, melanoma), expression analysis LRRK2 (leucine-rich repeat kinase 2) (eg, Parkinson disease), common variants (eg, R1441G, G2019S, I2020T) MED12 (mediator complex subunit 12) (eg, FG syndrome type 1, Lujan syndrome), common variants (eg, R961W, N1007S) MEG3/DLK1 (maternally expressed 3 [non-protein coding]/delta-like 1 homolog [Drosophila]) (eg, intrauterine growth retardation), methylation analysis MLL/AFF1 (t(4;11)) (eg, acute lymphoblastic leukemia), translocation analysis, qualitative, and quantitative, if performed MLL/MLLT3 (t(9;11)) (eg, acute myeloid leukemia), translocation analysis, qualitative, and quantitative, if performed MT-ATP6 (mitochondrially encoded ATP synthase 6) (eg, neuropathy with ataxia and retinitis pigmentosa [NARP], Leigh syndrome), common variants (eg, m.8993T&gt;G, m.8993T&gt;C) MT-ND4, MT-ND6 (mitochondrially encoded NADH dehydrogenase 4, mitochondrially encoded NADH dehydrogenase 6) (eg, Leber hereditary optic neuropathy [LHON]), common variants (eg, m.11778G&gt;A, m.3460G&gt;A, m.14484T&gt;C) MT-ND5 (mitochondrially encoded tRNA leucine 1 [UUA/G], mitochondrially encoded NADH dehydrogenase 5) (eg, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes [MELAS]), common variants (eg, m.3243A&gt;G, m.3271T&gt;C, m.3252A&gt;G, m.13513G&gt;A) MT-RNR1 (mitochondrially encoded 12S RNA) (eg, nonsyndromic hearing loss), common variants (eg, m.1555A&gt;G, m.1494C&gt;T) MT-TK (mitochondrially encoded tRNA lysine) (eg, myoclonic epilepsy with ragged-red fibers [MERRF]), common variants (eg, m.8344A&gt;G, m.8356T&gt;C) MT-TL1 (mitochondrially encoded tRNA leucine 1 [UUA/G]) (eg, diabetes and hearing loss), common variants (eg, m.3243A&gt;G, m.14709 T&gt;C) MT-TL1 MT-TS1, MT-RNR1 (mitochondrially encoded tRNA serine 1 [UCN], mitochondrially encoded 12S RNA) (eg, nonsyndromic sensorineural deafness [including aminoglycoside-induced nonsyndromic deafness]), common variants (eg, m.7445A&gt;G, m.1555A&gt;G) MUTYH (mutY homolog [E. coli]) (eg, MYH-associated polyposis), common variants (eg, Y165C, G382D) NOD2 (nucleotide-binding oligomerization domain containing 2) (eg, Crohn's disease, Blau syndrome), common variants (eg, SNP 8, SNP 12, SNP 13) NPM1/ALK (t(2;5)) (eg, anaplastic large cell lymphoma), translocation analysis PAX8/PPARG (t(2;3) (q13;p25)) (eg, follicular thyroid carcinoma), translocation analysis PRAME (preferentially expressed antigen in melanoma) (eg, melanoma), expression analysis PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), common variants (eg, N29I, A16V, R122H) PYGM (phosphorylase, glycogen, muscle) (eg, glycogen storage disease type V, McArdle disease), common variants (eg, R50X, G205S) RUNX1/RUNX1T1 (t(8;21)) (eg, acute myeloid leukemia) translocation analysis, qualitative, and quantitative, if performed SS18/SSX1 (t(X;18)) (eg, synovial sarcoma), translocation analysis, qualitative, and quantitative, if performed SS18/SSX2 (t(X;18)) (eg, synovial sarcoma), translocation analysis, qualitative, and quantitative, if performed VWF (von Willebrand factor) (eg, von Willebrand disease type 2N), common variants (eg, T791M, R816W, R854Q)
81404Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) ACADS (acyl-CoA dehydrogenase, C-2 to C-3 short chain) (eg, short chain acyl-CoA dehydrogenase deficiency), targeted sequence analysis (eg, exons 5 and 6) AQP2 (aquaporin 2 [collecting duct]) (eg, nephrogenic diabetes insipidus), full gene sequence ARX (aristaless related homeobox) (eg, X-linked lissencephaly with ambiguous genitalia, X-linked mental retardation), full gene sequence AVPR2 (arginine vasopressin receptor 2) (eg, nephrogenic diabetes insipidus), full gene sequence BBS10 (Bardet-Biedl syndrome 10) (eg, Bardet-Biedl syndrome), full gene sequence BTD (biotinidase) (eg, biotinidase deficiency), full gene sequence C10orf2 (chromosome 10 open reading frame 2) (eg, mitochondrial DNA depletion syndrome), full gene sequence CAV3 (caveolin 3) (eg, CAV3-related distal myopathy, limb-girdle muscular dystrophy type 1C), full gene sequence CD40LG (CD40 ligand) (eg, X-linked hyper IgM syndrome), full gene sequence CDKN2A (cyclin-dependent kinase inhibitor 2A) (eg, CDKN2A-related cutaneous malignant melanoma, familial atypical mole-malignant melanoma syndrome), full gene sequence CLRN1 (clarin 1) (eg, Usher syndrome, type 3), full gene sequence COX6B1 (cytochrome c oxidase subunit VIb polypeptide 1) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence CPT2 (carnitine palmitoyltransferase 2) (eg, carnitine palmitoyltransferase II deficiency), full gene sequence CRX (cone-rod homeobox) (eg, cone-rod dystrophy 2, Leber congenital amaurosis), full gene sequence CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1) (eg, primary congenital glaucoma), full gene sequence EGR2 (early growth response 2) (eg, Charcot-Marie-Tooth), full gene sequence EMD (emerin) (eg, Emery-Dreifuss muscular dystrophy), duplication/deletion analysis EPM2A (epilepsy, progressive myoclonus type 2A, Lafora disease [laforin]) (eg, progressive myoclonus epilepsy), full gene sequence FGF23 (fibroblast growth factor 23) (eg, hypophosphatemic rickets), full gene sequence FGFR2 (fibroblast growth factor receptor 2) (eg, craniosynostosis, Apert syndrome, Crouzon syndrome), targeted sequence analysis (eg, exons 8, 10) FGFR3 (fibroblast growth factor receptor 3) (eg, achondroplasia, hypochondroplasia), targeted sequence analysis (eg, exons 8, 11, 12, 13) FHL1 (four and a half LIM domains 1) (eg, Emery-Dreifuss muscular dystrophy), full gene sequence FKRP (fukutin related protein) (eg, congenital muscular dystrophy type 1C [MDC1C], limb-girdle muscular dystrophy [LGMD] type 2I), full gene sequence FOXG1 (forkhead box G1) (eg, Rett syndrome), full gene sequence FSHMD1A (facioscapulohumeral muscular dystrophy 1A) (eg, facioscapulohumeral muscular dystrophy), evaluation to detect abnormal (eg, deleted) alleles FSHMD1A (facioscapulohumeral muscular dystrophy 1A) (eg, facioscapulohumeral muscular dystrophy), characterization of haplotype(s) (ie, chromosome 4A and 4B haplotypes) GH1 (growth hormone 1) (eg, growth hormone deficiency), full gene sequence GP1BB (glycoprotein Ib [platelet], beta polypeptide) (eg, Bernard-Soulier syndrome type B), full gene sequence (For common deletion variants of alpha globin 1 and alpha globin 2 genes, use 81257) HNF1B (HNF1 homeobox B) (eg, maturity-onset diabetes of the young [MODY]), duplication/deletion analysis HRAS (v-Ha-ras Harvey rat sarcoma viral oncogene homolog) (eg, Costello syndrome), full gene sequence HSD3B2 (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2) (eg, 3-beta-hydroxysteroid dehydrogenase type II deficiency), full gene sequence HSD11B2 (hydroxysteroid [11-beta] dehydrogenase 2) (eg, mineralocorticoid excess syndrome), full gene sequence HSPB1 (heat shock 27kDa protein 1) (eg, Charcot-Marie-Tooth disease), full gene sequence INS (insulin) (eg, diabetes mellitus), full gene sequence KCNJ1 (potassium inwardly-rectifying channel, subfamily J, member 1) (eg, Bartter syndrome), full gene sequence KCNJ10 (potassium inwardly-rectifying channel, subfamily J, member 10) (eg, SeSAME syndrome, EAST syndrome, sensorineural hearing loss), full gene sequence LITAF (lipopolysaccharide-induced TNF factor) (eg, Charcot-Marie-Tooth), full gene sequence MEFV (Mediterranean fever) (eg, familial Mediterranean fever), full gene sequence MEN1 (multiple endocrine neoplasia I) (eg, multiple endocrine neoplasia type 1, Wermer syndrome), duplication/deletion analysis MMACHC (methylmalonic aciduria [cobalamin deficiency] cblC type, with homocystinuria) (eg, methylmalonic acidemia and homocystinuria), full gene sequence MPV17 (MpV17 mitochondrial inner membrane protein) (eg, mitochondrial DNA depletion syndrome), duplication/deletion analysis NDP (Norrie disease [pseudoglioma]) (eg, Norrie disease), full gene sequence NDUFA1 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 1, 7.5kDa) (eg, Leigh syndrome, mitochondrial complex I deficiency), full gene sequence NDUFAF2 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, assembly factor 2) (eg, Leigh syndrome, mitochondrial complex I deficiency), full gene sequence NDUFS4 (NADH dehydrogenase [ubiquinone] Fe-S protein 4, 18kDa [NADH-coenzyme Q reductase]) (eg, Leigh syndrome, mitochondrial complex I deficiency), full gene sequence NIPA1 (non-imprinted in Prader-Willi/Angelman syndrome 1) (eg, spastic paraplegia), full gene sequence NLGN4X (neuroligin 4, X-linked) (eg, autism spectrum disorders), duplication/deletion analysis NPC2 (Niemann-Pick disease, type C2 [epididymal secretory protein E1]) (eg, Niemann-Pick disease type C2), full gene sequence NR0B1 (nuclear receptor subfamily 0, group B, member 1) (eg, congenital adrenal hypoplasia), full gene sequence PDX1 (pancreatic and duodenal homeobox 1) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence PHOX2B (paired-like homeobox 2b) (eg, congenital central hypoventilation syndrome), full gene sequence PLP1 (proteolipid protein 1) (eg, Pelizaeus-Merzbacher disease, spastic paraplegia), duplication/deletion analysis PQBP1 (polyglutamine binding protein 1) (eg, Renpenning syndrome), duplication/deletion analysis PRNP (prion protein) (eg, genetic prion disease), full gene sequence PROP1 (PROP paired-like homeobox 1) (eg, combined pituitary hormone deficiency), full gene sequence PRPH2 (peripherin 2 [retinal degeneration, slow]) (eg, retinitis pigmentosa), full gene sequence PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), full gene sequence RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1) (eg, LEOPARD syndrome), targeted sequence analysis (eg, exons 7, 12, 14, 17) RET (ret proto-oncogene) (eg, multiple endocrine neoplasia, type 2B and familial medullary thyroid carcinoma), common variants (eg, M918T, 2647_2648delinsTT, A883F) RHO (rhodopsin) (eg, retinitis pigmentosa), full gene sequence RP1 (retinitis pigmentosa 1) (eg, retinitis pigmentosa), full gene sequence SCN1B (sodium channel, voltage-gated, type I, beta) (eg, Brugada syndrome), full gene sequence SCO2 (SCO cytochrome oxidase deficient homolog 2 [SCO1L]) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence SDHC (succinate dehydrogenase complex, subunit C, integral membrane protein, 15kDa) (eg, hereditary paraganglioma-pheochromocytoma syndrome), duplication/deletion analysis SDHD (succinate dehydrogenase complex, subunit D, integral membrane protein) (eg, hereditary paraganglioma), full gene sequence SGCG (sarcoglycan, gamma [35kDa dystrophin-associated glycoprotein]) (eg, limb-girdle muscular dystrophy), duplication/deletion analysis SH2D1A (SH2 domain containing 1A) (eg, X-linked lymphoproliferative syndrome), full gene sequence SLC16A2 (solute carrier family 16, member 2 [thyroid hormone transporter]) (eg, specific thyroid hormone
81405Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) Cytogenomic constitutional targeted microarray analysis of chromosome 22q13 by interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities (When performing cytogenomic [genome-wide] analysis, for constitutional chromosomal abnormalities. See 81228, 81229, 81349)
81479Unlisted molecular pathology procedure

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