Friday, November 15, 2019

CPT H1001, H1001, H1003 - Prenatal care


CPT CODE and Description

H1000  PRENATAL CARE, AT-RISK ASSESSMENT
H1001 Prenatal care, at-risk enhanced service; antepartum management
H1003 Prenatal care, at-risk enhanced service; education



HCPCS Code  H1000 - Prenatal care atriskassessm


Risk Assessment 

Risk assessment is the systematic review of relevant member data to identify potential problems and determine a plan for care.  Early identification of high risk pregnancies with appropriate consultation and intervention contributes significantly to an improved perinatal outcome and lowering of maternal and infant morbidity and mortality.   A care plan for high risk members, in addition to standard care, includes referral to or consultation with an appropriate specialist, individualized counseling and services designed to address the risk factor(s) involved.  A care plan for low risk members includes primary care services and additional services specific to the needs of the individual.  

Risk Assessments may be provided by one of the following licensed Medicaid providers:

**   Physician
**   Certified Nurse Practitioner
**   Certified Nurse-Midwife

The service is reported using HCPCS H1000 Prenatal Care, At Risk Assessment for a low risk assessment or HCPCS H1001 Prenatal Care, At Risk Enhances Service; Antepartum Management for high risk assessment.  Limited to two (2) assessments during any 10-month period.

Single Prenatal Visit(s) Other than Initial Visit

A single prenatal visit other than the initial visit is a single prenatal visit for an established member who does not return to complete care for unknown reasons.  The initial assessment visit was completed, a plan of care established, one or two follow-up visits completed, without further care provided.

Single Prenatal Visit may be provided by one of the following licensed Medicaid providers:

**   Physician
**   Certified Nurse Practitioner
**   Certified Nurse-Midwife 

The service is reported using an appropriate CPT E/M code.  Limited to three (3) visits in any 10-month period.  The service may be billed only when the member is lost to follow up for any reason.  


Prenatal Assessment Visit (Initial Visit Only)

The initial prenatal assessment visit is a single prenatal visit for a new patient with a confirmed pregnancy, providing an evaluation of the mental and physical status of the patient, an in depth family and medical history, physical examination, development of the medical data and initiation of a plan of care.  
Prenatal Assessment Visit may be provided by one of the following licensed Medicaid providers:

**   Physician
**   Certified Nurse Practitioner
**   Certified Nurse-Midwife 

The service is reported using an appropriate CPT E/M code.  Limited to one (1) visit in any 10-month period, to be used only when the patient is referred immediately to a community practitioner because of identified risks or otherwise lost to follow-up because the patient does not return. 

Billing Guidelines from Uhc

Florida

** Prenatal care must be billed separately from the delivery and postpartum care.
** FL providers are to submit prenatal codes H1001 and/or H1000.
** Up to 10 visits are allowed for prenatal care.** Up to two postpartum visits are allowed within 90 days following delivery, per recipient.
** Delivery of two or more infants from a single pregnancy, by different delivery method, separately.  Same delivery method is non-covered


BCBS insurance Guidelines

Pre-term Birth Prevention Services


Blue Cross will reimburse for certain pre-term birth prevention serviceswhen the patient’s contract covers these services.

CODE                     NARRATIVE               BILLING
H1001       Prenatal care, at-risk enhancedservice; antepartum management        If the patient isidentified via the assessment as high risk. This code may be billed once.

H1003       Prenatal care, at-risk enhanced                            If the patient isidentified via the assessment as high risk. This code may be billed once.




The services represented by the prenatal care at-risk codes H1002, H1004 and H1005 are already included in the provider’s normal prenatal care and not separately reimbursed.



All Prenatal visits must be billed using the appropriate E&M code for each prenatal visit.  Specific CPT and  HCPCS  Codes  are  listed.   MFC  has  included  a  list  of  CPT  Codes  provided  by  MDH.   This  list  is subject to change at any time without notice when MDH updates their On-Line information.

** Delivery services can be billed 1 of 2 ways: o Delivery Service + Post Partum Care o Delivery Services Only

** Providers may bill: o H1000 (Risk Assessment) once per pregnancy o H1003  (Enhanced  Services)  once  per  visit  for  Maryland  Medicaid  members.   Providers  must document in the medical record that health education and counseling appropriate to the needs of the pregnant woman was provided.

** OBs must bill for circumcisions under the infant’s own name and Medicaid Number /MFC Number.** For procedure codes with a global value MMM, the global period equals 56 days.

** When a provider bills a delivery + post partum care at the time of delivery, the provider must rebill using the exact same codes when the post partum visit actually takes place and adding the modifier TH to the claim.  Use of this modifier however will indicate he date that the postpartum visit actually occurred.  The postpartum visit has to occur on or between 21 and 56 days after delivery. ** If the provider bills the delivery only code, and then later bills the delivery + postpartum code to indicate that  the  postpartum  visit  occurred,  the  original  delivery  only  payment  is  retracted  and  the  delivery  + postpartum code billed is paid

Timeliness of Prenatal Care

Measurement: Deliveries  that  received  prenatal  care  visit  in  the  first  trimester  or  within  42  days of enrollment in a health plan.

Required documentation in the medical record for PRENATAL care visit:

1)A basic physical obstetrical examination that includes

** Auscultation for fetal heart tone, or ** Pelvic exam with obstetric observations, or
** Measurement of fundus height (a standardized prenatal flow sheet may be used)

2)Prenatal Care Procedure: Could be:
** Screening test/obstetric panel or ** TORCH antibody panel alone, or
** A rubella antibody test/titer with an Rh incompatibility (ABO/Rh) blood typing, or
** Ultrasound/Echography of a pregnant uterus

3)Documentation  of  LMP  or  EDD  with either prenatal  risk  assessment  &  counseling/education, or complete obstetrical history

Required coding for PRENATAL care visit:

Stand Alone Prenatal Visits
CPT: 59425, 59426,99201-99205, 99211-99215, 99241-99245, 99500
CPT II: 0500F, 0501F, 0502F
HCPCS: H1000, H1001, H1002, H1003, H1004

Tuesday, October 15, 2019

CPT H0001, H0004, H0002, H0005, H0046, H0046

CPT code and Description

H0001 Alcohol and/or drug assessment
H0004 Behavioral health counseling and therapy (15 min)
H0002 Behavioral health screening to determine eligibility for admission to treatment program 
H0005 Alcohol and/or drug services; group counseling by a clinician
H0046 Mental Health Services, Not Otherwise Specified (60 Min)
H0047 Alcohol and/or other drug abuse services, not otherwise specified


Billing Guidelines

CPT H0046- Direct communications with the client and/or collaterals designed to help an enrolled individual attain goals as prescribed in his/her individual service plan. Usage is limited to medically necessary contacts less than 10 minutes that cannot otherwise be reported elsewhere. (Excludes: reminder (non-therapeutic) phone calls, listening to voice mails, e-mails)

For example, a clinician providing a half-hour of individual psychotherapy may code the service as 90832 (Psychotherapy, 30 min with patient and/or family member). If, however, the client leaves after 10 minutes, coding 90832 for that service would not meet fidelity for that code. It would not only be difficult to contend that insight-oriented, behavior modifying or supportive psychotherapy had been provided during such a short time, and CPT guidelines specifically require a minimum of 16 minutes for the use of this code. The service could be coded and reported using H0046, “Mental Health Services Not Otherwise Specified,” which can be reported in minutes. See Individual Treatment services modality for H0046 usage limitations.

CPT H0047 - Direct communications with the client and/or collaterals designed to help an enrolled individual attain goals as prescribed in his/her individual service plan. (Excludes: reminder (non-therapeutic) phone calls, listening to voice mails, e-mails) For Medicaid funded services, this service may only be provided by a CDP or CDPT.

If H0046 (Mental health services, not otherwise specified) is provided for 9 minutes, report 9 minutes.

If H0047 (Alcohol and/or other drug abuse services, not otherwise specified) is provided for 7 minutes, report 7 minutes.

CPT H0001 - Must be doneface-to-face. Provider type - 20-Chemical Dependency Professional  21-Chemical Dependency Professional Trainee

CPT H004 - 10 Minutes minimumfor first unit - Provider type - 20-Chemical Dependency Professional  21-Chemical Dependency Professional Trainee. 01-RN/LPN  02-ARNP/PA   03-Psychiatrist/MD   04-MA/Ph.D.   05-Below Masters Degree  09-Bachelors Level w/Exception Waiver   10-Master Level w/Exception Waiver.



Reimbursement Guidelines from UHC insurance


Documentation maybe reviewed for appropriate coding, existence of a more appropriate code, coverage, reimbursement allowance and prior notification if needed. Unlisted codes that do not have documentation will be denied.

Texas 

Documentation and review not needed for:
** 99429,State requires providers to bill unlisted code 99429 whenproviding dental varnish
** A4335 when billed with an U9 modifier
** H0046when billed by an FQHC for Texas MMP
** H0046 when billed for Texas Chip, Star Kidsand Star Plus** B9998 when billed with modifiers U1-U5



SUBSTANCE ABUSE PROCEDURE CODES

H0001  Alcohol  and/or  drug  assessment  – means  the  evaluation  of  an  individual  by  a clinician to determine the presence, nature, and extent of substance use disorder with the goal of formulating a plan for services (if such services are offered) and treating the client in the most appropriate treatment environment.

H0003 Alcohol and/or drug screening; laboratory analysis of specimens for presence of alcohol and/or drugs – means the laboratory testing of client specimens to detect the presence of alcohol and other drugs.

H0005  Alcohol  and/or  drug  services;  group  counseling  by  a  clinician –  means services   provided   by   a   clinician   to   assist two or more individuals and/or their families/significant  others  to  achieve  treatment  objectives  through  the  exploration  of substance use disorders and their ramifications, including an examination of attitudes and feelings, and considering alternative solutions and decision making with regard to alcohol and other drug related problems.

H0006 Alcohol and/or drug services; case management – means services provided to link individuals to, or to assist and support clients in gaining access to or to develop their skills  for  gaining  access  to  needed  medical,  social,  educational  and  other  services essential to meeting basic human needs, as appropriate; to train the individual in the use of  basic  community  services;  and  to  monitor  treatment  progress  and  overall  service delivery. 

H0007 Alcohol and/or drug services; crisis intervention (outpatient) – means a face-to-face response to a crisis or emergency situation experienced by an individual, family member and/or significant others related to substance use disorders.

H0008 Alcohol and/or drug services; sub-acute detoxification (hospital inpatient) –  means face-to-face interactions with an individual for the purpose of medically managing and  monitoring  withdrawal  symptoms  from  alcohol  and/or  drug  addiction  in  a  hospital with appropriate accreditation, certification, and licensure, staffed with a registered nurse on  the  premises  twenty-four  hours  per  day  and  a  licensed  physician  on  call  twenty-four hours per day. Detoxification services must be supervised by a licensed physician. 



Q:Will UnitedHealthcare reimburse more than one presumptive and/or one definitive drug test on the same date of service if a modifier is appended?
A:No, each of the presumptive and definitive drug codes define a single manual or automated laboratory service that is reported once per day, per patient,irrespective of the number of Drug Classes, sample validations, or Specimen Validity Testsperformed related to that service on any date of service. In accordance with the CPT and CMS guidelines UnitedHealthcare will not reimburse more than one presumptive and/or one definitive drug test per dayregardless of the number of billing providers.


Presumptive Codes

H0003  Alcohol and/or drug screening; laboratory analysis of specimens for presence of alcohol and/or drugs(The H  codes are used by those state Medicaid agencies that are mandated by state law to establish separate codes for identifying mental health services that include alcohol and drug treatment services.)



Prenatal and Postnatal Psychosocial Counseling  


Psychosocial evaluation is provided as a prenatal and postnatal service to identify members and families with high psychological and social risks, to develop a psychosocial care plan and provide or coordinate appropriate intervention, counseling or referral necessary to meet the identified needs of each family.  
Counseling may be provided by one of the following licensed Medicaid providers:

**   Licensed Clinical Social Worker
**   Clinical Psychologist
**   Marriage and Family Therapist

The service is reported using HCPCS H0046 Mental Health Services, Not Otherwise Specified.  Limited to twelve (12) visits during any 12-month period. 

Monday, July 15, 2019

CPT 76705 AND 76706

Procedure Code(s) and Description

76705 Ultrasound, abdominal, real time with image documentation; limited (eg, single organ, quadrant,  follow-up)

76706  Ultrasound Screening Study for Abdominal Aortic Aneurysm


Preventive Benefit Instructions

Age 65 through 75 (ends on 76thbirthday). Requires at least one of the diagnosis codes listed in this row

Diagnosis Code(s)- covered ICD 10 codes

F17.210, F17.211, F17.213, F17.218, F17.219, Z87.891


Medicare guidelines for using AAA screen


Effective for services furnished on or after January 1, 2017, the following code and modifiers, are used for AAA screening services:76706: Ultrasound, abdominal aorta, real time with image documentation, screening study for abdominal aortic aneurysm (AAA). (For screening ultrasound or duplex ultrasound of the abdominal aorta other than screening, see 76770, 76775, 93978, 93979.)

Short Descriptor:  Us abdl aorta screen AAA

Modifiers:  TC, 26


Fee amount for technical and professional component

CPT 76705
Professional $30.24
Technical $63.72
Global$93.96


CPT 76706
Professional $28.44
Technical$68.40
Global$96.84


Documentation Requirements

Ultrasound performed using either a compact portable  ultrasound or a console ultrasound system are reported  using the same CPT codes as long as the studies that were  performed meet all the following requirements:

• Medical necessity as determined by the payer
• Completeness
• Documented in the patient’s medical record

A separate written record of the diagnostic ultrasound  or ultrasound-guided procedure must be completed and  maintained in the patient record.7 This should include a  description of the structures or organs examined and the  findings and reason for the ultrasound procedure(s).  Diagnostic ultrasound procedures require the production and retention of image documentation. It is recommended that permanent ultrasound images, either electronic or hardcopy, from all ultrasound services be retained in the patient record  or other appropriate archive.


Coverage

Use of ultrasound-guided procedures may be a covered benefit if such usage meets all requirements established by the particular payer. In many cases, because the use of ultrasound guidance is an emerging technology, it may be considered investigational and may not be a covered procedure.It is advisable that you check with your local Medicare Contractor. Also, it is essential that each claim be coded appropriately and supported with adequate documentation in the medical record.

Coverage by private payers varies by payer and by plan with respect to which medical specialties may perform ultrasound services. Some payers will reimburse ultrasound procedures to all specialties while other plans will limit reimbursement for ultrasound procedures to specific types of medical specialties.


In addition, there are plans that require providers to submit applications requesting these services be added to the list of services performed in their practice. It is important that you contact the payer prior to submitting claims to determine their requirements



Saturday, June 29, 2019

cpt 81223, 81257, 81258, 81269, 81412 - Preconception Screening


Code Description CPT 

81223 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g., cystic fibrosis) gene analysis; full gene sequence

81257 HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis, for common deletions or variant (eg, Southeast Asian, Thai, Filipino, Mediterranean, alpha3.7, alpha4.2, alpha20.5, and Constant Spring) (effective 1/1/18)

81258 HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; known familial variant (effective 1/1/18)

81259 HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; full gene sequence (effective 1/1/18)

81269 HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; duplication/deletion variants (effective 1/1/18)

81412 Ashkenazi Jewish associated disorders (eg, Bloom syndrome, Canavan disease, cystic fibrosis, familial dysautonomia, Fanconi anemia group C, Gaucher disease, Tay-Sachs disease), genomic sequence analysis panel, must include sequencing of at least 9 genes, including ASPA, BLM, CFTR, FANCC, GBA, HEXA, IKBKAP, MCOLN1, and SMPD1

81479 Unlisted molecular pathology procedure


What are MoPath Codes?

MoPath codes are labels for molecular diagnostics tests that enable payers (i.e., Medicare, Medicaid, private insurance companies) to properly identify and bill for services. In 2012, the AMA CPT estab-lished a new set of analyte-specific MoPath codes to replace the methodology-based codes (CPT 83890-83914; 88384-88386) that previously allowed labs to bill different coding combinations (also known as “code stacks”) for tests evaluating the same analyte. These “stacking” codes were retired as of January 1, 2013. Labs are now required to report tests using the analyte-specific  MoPath codes.

The MoPath codes are categorized into Tier 1 and Tier 2 codes:

•  Tier 1 codes represent the majority of commonly performed single-analyte molecular tests.

•  Tier 2  codes represent procedures that are generally performed in  lower volumes than Tier 1 procedures (e.g., when the incidence of  the disease being tested is rare), and correspond to nine ascending levels of technical resources and interpretive work performed by the  physician or other qualified healthcare professional


Coverage

In general, CF genetic testing is widely covered for both carrier  screening and confirmatory diagnostic testing (Figures 1 and 2). Private payers generally separate coverage guidelines for CF carrier screening versus confirmatory diagnostic testing. For both indica-tions, the majority of payers have either issued positive coverage policies or no policies at all. The absence of a coverage policy does not necessarily indicate non-coverage, but implies that the procedure may be covered if medical necessity can be justified.


Based on private payer coverage guidelines, CF carrier screening is generally covered for individuals who meet any of the following criteria:

• Couples seeking prenatal care

•  Couples who are planning a pregnancy

•  Persons with a family history of CF

•  Persons with a 1st degree relative identified as a CF carrier

•  Reproductive partners of persons with CF Additionally, CF diagnostic testing is typically covered for individuals

who meet any of the following criteria:

• Individual who exhibits symptoms of CF but has a negative sweat test

• Infant with meconium ileus or other symptoms indicative of CF who is too young to produce inadequate volumes of sweat for a sweat chloride test 

•  Male infertility from either of the following:

- Congenital bilateral absence of vas deferens (CBAVD)

- Azoospermia or severe oligospermia  (i.e., < 5 million sperm/milliliter) with palpable vas deferens The majority of state Medicaid agencies do not have policies specifi-cally addressing coverage for CF genetic testing (carrier screening  or diagnostic testing), but instead have general coverage policies for  laboratory services performed by CLIA-approved labs.


Payment
For 2013, the Centers for Medicare & Medicaid Services (CMS) assigned the local Medicare Administrative Contractors (MACs) the responsibility of setting regional fee schedule amounts for the new MoPath code set (including payment rates for CF testing) via gapfilling.Gapfilling is used when a comparable test does not exist. CMS instructs local MACs to establish payment rates in the first year based on charges and routine discounts to charges, resources required, and other payers’ payment rates. For reimbursement in the second year and beyond, CMS calculates a national payment rate by using the median of the local MAC fee schedules.On September 30, 2013, CMS released the 2014 national Medicare fee schedule amounts for the MoPath codes, which were based on the final gapfill rates determined by each MAC

.  However, the national fee schedule did not include any payment rates for the cystic fibrosis testing codes. Since payment rates will vary by payer (both private and public), laboratories are encouraged to contact individual payers directly to clarify the fee schedule amounts for these codes in 2014.


Preconception Screening for Carrier Status of Genetic Diseases

Introduction


Genetic tests are laboratory tests that measure changes in human DNA, chromosomes, genes or gene products (proteins). Blood, skin, cheek swabs, and amniotic fluid are some common samples that can be tested. Genetic testing for carrier status is done on people planning a pregnancy. The goal is to see if they have a potential disease that could be passed on to their offspring. For certain disorders, a carrier state can exist where a person has no symptoms of the disease, but has the potential to pass the disease on to their children because they carry a gene for the disease. Often it takes at least two copies of the gene for the disease to cause symptoms. Usually carrier testing is done before conception when individuals are planning a pregnancy, but it may also be done in the early stages of pregnancy.



Policy Coverage Criteria 

This policy applies only if there is not a separate policy that outlines specific criteria for carrier testing. If a separate policy exists, then criteria for medical necessity in that policy supersedes the guidelines in this policy (see Related Policies).
Note: Usually carrier testing is done before conception when individuals are planning a pregnancy, but it may also be done in the early stages of pregnancy.
Test Type Medical Necessity Expanded Carrier

Expanded Carrier Screening Panels

Expanded carrier screening panels which test for mutations on many different genes are considered not medically necessary. Based on the individual tested, a subset of tests within the panel may be covered when the policy criteria are met.

The names of expanded carrier panels, and their individual mutation components, are rapidly evolving. Examples of panels addressed in this policy include but are not limited to: * Counsyl™ (Counsyl) * GoodStart Select™ (GoodStart Genetics) * Inherigen™ (GenPath) * InheriGen Plus * Inheritest™ (LabCorp) * Natera One™ Disease Panel (Natera)  Genetic Disease Medical Necessity The General Population  Cystic fibrosis (CPT 81220) Covered for all individuals with a panel that tests the most common genes 

Note: Carrier testing for cystic fibrosis using CPT 81223 “CFTR (eg, cystic fibrosis) gene analysis; full gene sequence” is considered not medically necessary for carrier testing.


Genetic Disease Medical Necessity  Spinal muscular atrophy (CPT 81400, 81401)

Covered for all individuals

Genetic Disease Medical Necessity Specific Groups or Populations

The following genetic testing may also be considered medically necessary due to an increased frequency of certain disorders in groups or populations
Ashkenazi Jewish founder mutations:

* Bloom syndrome  * Canavan disease  * Cystic fibrosis  * Familial dysautonomia  * Fanconi anemia (group C)  * Gaucher disease * Mucolipidosis IV  * Niemann-Pick (type A)

* Tay-Sachs disease

FMR1 variants (including Fragile-X syndrome)

Ashkenazi Jewish founder mutations may be considered medically necessary when the individual meets one of the following criteria: * Ashkenazi Jewish ancestry consisting of a minimum of one
Jewish grandparent * If the Jewish partner has a positive carrier test result, the other
partner (regardless of ethnic background) should be screened only for that identified mutation

Genetic testing for Ashkenazi Jewish founder mutation is considered not medically necessary for all other uses.

Genetic testing for FMR1 variants may be considered medically necessary when any of the following criteria are met: * Parent of either sex with intellectual disability, developmental delay, or autism spectrum disorder * Parent with a family history of fragile X syndrome or a family  history of undiagnosed intellectual disability  * Prenatal testing of fetuses of mothers  who are known carriers   to determine whether the fetus inherited the normal or mutant FMR1 gene

* Affected individuals or first- and second- degree relatives   of affected individuals who have had a positive cytogenetic fragile X test (less accurate historic test) result who are seeking further counseling related to the risk of carrier status

Genetic testing for FMR1 variants (including Fragile-X syndrome) is considered not medically necessary for all other

Genetic Disease Medical Necessity  uses.  Alpha-thalassemia

preconception (carrier) testing


Preconception (carrier) testing for alpha-thalassemia in prospective parents may be considered medically necessary when all of the following criteria are met: * At least one parent is of a high-risk ethnic group, such as
Southeast Asian, African or Mediterranean ancestry * At least one parent has had abnormal biochemical testing
which may include ANY of the following: o Anemia o Microcytosis (a low MCV – small blood cells) o Hypochromia (a low MCH or MCHC – red blood cells with
less hemoglobin) o Abnormal hemoglobin electrophoresis

Genetic testing for hemoglobinopathies, except for alphathalassemia, is considered not medically necessary.
Genetic Disease Medical Necessity Other Inherited Disorders

Carrier testing of specific disorder

May be considered medically necessary when ONE of the following criteria are present: * One or both parents have a first-  or second-degree relative*
who has the disorder * One parent is or both parents are a known carrier of the
disorder. 

Note: 1st-degree relatives are parents, siblings, and children. 2nd-degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings. 

AND all of the following criteria must also be met: * The natural history of the disease is understood and the
disease is likely to result in severe health problems * Other biochemical or clinical tests to diagnose carrier status are


Genetic Disease Medical Necessity Coding not available, or are less accurate than genetic testing * The genetic test has adequate sensitivity and specificity to guide clinical decision making  o The American College of Medical Genetics and Genomics (ACMG) recommends testing for specific mutations, which will result in carrier detection rate of 95% or higher for most disorders.

* A clear association of the genetic change with the disorder has been established Genetic testing for other specific disorders is considered not medically necessary when the criteria above are not met.




Related Information 

If there is no family history of, risk based or ethnic predilection for a disease, carrier screening is not recommended when the carrier rate is less than 1% in the general population.

ACMG has defined expanded panels as those that use next-generation sequencing to screen for variants in many genes, as opposed to gene-by-gene screening (eg, ethnic-specific screening or pan-ethnic testing for cystic fibrosis).
Expanded panels may include the diseases that are present with increased frequency in specific populations, but typically include testing for a wide range of diseases for which the patient is not at risk of being a carrier.
Carrier screening should only be performed in adults. 

For individuals who are at risk due to an established family history of fragile X syndrome, DNA testing alone is sufficient. If the diagnosis of the affected relative was based on previous cytogenetic testing for fragile X syndrome, at least one affected relative should have DNA testing.
Prenatal testing of a fetus should be offered when the mother is a known carrier to determine whether the fetus inherited the normal or mutant FMR1 gene. Ideally DNA testing should be performed on cultured amniocytes obtained by amniocentesis after 15 weeks’ gestation. DNA testing can be performed on chorionic villi obtained by chorionic villus sampling at 10 to 12 weeks’ gestation, but results must be interpreted with caution because the methylation status of the FMR1 gene is often not yet established in chorionic villi at the time of sampling. follow-up amniocentesis may be necessary to resolve an ambiguous result.


Definition of Terms


1st-, 2nd-, or 3rd-degree relative: For the purpose of familial assessment, 1st-, 2nd-, or 3rddegree relatives are blood relatives on the same side of the family (maternal or paternal). The maternal and paternal sides of the family should be considered independently for familial patterns of inherited disorders. 

* 1st-degree relatives are parents, siblings, and children.
* 2nd-degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings.
* 3rd-degree relatives are great-grandparents, great-aunts, great-uncles, great-grandchildren, and first cousins 
Carrier testing: Carrier genetic testing is performed on people who display no symptoms for a genetic disorder but may be at risk for passing it on to their children.
A carrier of a genetic disorder has one abnormal allele for a disorder.  Carriers of an autosomal recessive mutation are typically unaffected.  Offspring who inherit the mutation from both parents usually manifest the disorder. When associated with an autosomal dominant or an Xlinked dominant disorder, the individual may be affected with the disorder or be at high risk of developing the disorder later in life. Women with an X-linked recessive mutation are usually unaffected. Males receiving a chromosome with an X-linked recessive mutation usually manifest the disorder.
Compound heterozygous: The presence of two different mutant alleles at a particular gene locus, one on each chromosome of a pair.

Expressivity/expression: The degree to which a penetrant gene is expressed within an individual.
Genetic testing: A test that analyzes chromosomes, DNA, RNA, genes, or gene products to detect inherited (germline) or non-inherited (somatic) genetic variants related to disease or health

Homozygous: Having the same alleles at a particular gene locus on homologous chromosomes (chromosome pairs).
Penetrance: The proportion of individuals with a mutation that causes a particular disorder who exhibit clinical symptoms of that disorder.

Residual risk: The risk that an individual is a carrier of a particular disease, but genetic testing for carrier status of the disease is negative (eg, if the individual has a disease-causing mutation that wasn’t included in the test assay).

Testing sequence: Testing sequence of carrier testing for genetic diseases is generally done on the mother or affected partner first, and if positive, then the other parent is tested.

Genetics Nomenclature Update

Human Genome Variation Society (HGVS) nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics (see Table 1). HGVS nomenclature is recommended by HGVS, the Human Variome Project, and the HUman Genome Organization (HUGO).

The American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) standards and guidelines for interpretation of sequence variants represent expert opinion from ACMG, AMP, and the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA
Previous  Updated  Definition
Mutation Disease-associated variant Disease-associated change in the DNA sequence
Variant Change in the DNA sequence 
Familial variant Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives

Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification Definition
Pathogenic Disease-causing change in the DNA sequence

Variant Classification Definition 

Likely pathogenic Likely disease-causing change in the DNA sequence 
Variant of uncertain significance Change in DNA sequence with uncertain effects on disease
Likely benign Likely benign change in the DNA sequence
Benign Benign change in the DNA sequence
ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology. providing a diagnosis eliminates the need for further diagnostic workup. A chain of evidence supports improved outcomes following FMR1 variant testing.. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have a personal or family history of FXS who are seeking reproductive counseling, the evidence includes studies  evaluating the clinical validity of FMR1 variant testing and the effect on reproductive decision making. Testing the repeat region of the FMR1 gene in the context of reproductive decision making may include individuals with either a family history of FXS or a family history of undiagnosed intellectual disability, fetuses of known carrier mothers, or affected individuals or their relatives who have had a positive cytogenetic fragile X test result who are seeking further counseling related to the risk of carrier status among themselves or their relatives. DNA testing would accurately identify premutation carriers and distinguish premutation from full mutation carrier women. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.




Tuesday, June 18, 2019

(HCPCS Codes R0070 - , R0075, R0076) - Transportation Component

Procedure codes (CPT & HCPCS) :


CPT Code Code Description

R0070 Transportation of portable x-ray equipment and personnel to home or nursing home, per trip to facility or location, one patient seen

R0075 Transportation of portable x-ray equipment and personnel to home or nursing home, per trip to facility or location, more than one patient seen


Reimbursement Guidelines
Effective for claims processed on or after July 29, 2018,Moda Health follows CMS guidelines in  allowing a  single  transportation  payment  for  each  trip  the  portable  x - ray provider makes transporting  x-ray equipment to a particular location.(CMS  1 ) When more than one patient is x-rayed at the same location ( e.g.,  a  nursing  home ), the allowable  amount  for  the transportation  service  will  be  reduced  (prorated) based upon the total number of patients receiving the portable x - ray services during that trip, regardless of their insurance status.

* If only one patient is served,  report procedure code  R0070 with no modifier,since the descriptor for this code reflects only one patient seen. 

* If more than one patient receives portable x-ray services during that trip, report R0075, regardless of whether or not all the patients have insurance, or under which carrier.


Note: When the x-ray equipment used is actually transported to the location where the x-ray was taken, then a transportation service may be billed.  If the x-ray equipment used is stored in the location where the x-ray was done (e.g., a nursing home) for use as needed, then an equipmenttransportation service (R0070, R0075) may not be billed.

HCPCS code R0075 must be billed with one of the following modifiers, to indicate how many patients wereserved on that trip to the facility or location. The allowable fee forR0075 will be adjusted based upon the modifier used.

Modifier Modifier Definition  Payment Adjustment


Modifier  UN Two patients served D ivided by 2 (50%)

Modifier UP Three patients served Divided by 3 (33.3%)

Modifier UQ Four patients served Divided by 4 (25%)

Modifier UR Five patients served Divided by 5 (20%)

Modifier US Six patients or more served Divided by 6, regardless of the number of  patients served (16.7%)

This component represents the transportation of the equipment to the patient. Establish local RVUs for the transportation R codes based on carrier knowledge of the nature of the service furnished. Carriers shall allow only a single transportation payment for each trip the portable x-ray supplier makes to a particular location. When more than one Medicare patient is x-rayed at the same location, e.g., a nursing home, prorate the single fee schedule transportation payment among all patients receiving the services. For example, if two patients at the same location receive x-rays, make one-half of the transportation payment for each.

R0075 must be billed in conjunction with the Procedure code radiology codes (7000 series) and only when the x-ray equipment used was actually transported to the location where the x-ray was taken. R0075 would not apply to the x-ray equipment stored in the location where the x-ray was done (e.g., a nursing home) for use as needed.salary and fringe benefits of the staff who determine the vehicles route (this could be proportional of office staff), repairs and maintenance of the vehicle(s), insurance for the vehicle(s), operating expenses for the vehicles and any other reasonable costs associated with this service as determined by the carrier. The carrier will have discretion for allocating indirect costs (those costs that cannot be directly attributed to portable x-ray transportation) between the transportation service and the technical component of the x-ray tests.
Suppliers may send carriers unsolicited cost information. The carrier may use this cost data as a comparison to its carrier priced determination. The data supplied should reflect a year’s worth (either calendar or corporate fiscal) of information. Each provider who submits such data is to be informed that the data is subject to verification and will be used to supplement other information that is used to determine Medicare’s payment rate.

Carriers are required to update the rate on an annual basis using independently determined measures of the cost of providing the service. A number of readily available measures (e.g., ambulance inflation factor, the Medicare economic index) that are used by the Medicare program to adjust payment rates for other types of services may be appropriate to use to update the rate for years that the carrier does not recalibrate the payment. Each carrier has the flexibility to identify the index it will use to update the rate. In addition, the carrier can consider locally identified factors that are measured independently of CMS as an adjunct to the annual adjustment.

NOTE: No transportation charge is payable unless the portable x-ray equipment used was actually transported to the location where the x-ray was taken. For example, carriers do not allow a transportation charge when the x-ray equipment is stored in a nursing home for use as needed. However, a set-up payment (see §90.4, below) is payable in such situations. Further, for services furnished on or after January 1, 1997, carriers may not make separate payment under HCPCS code R0076 for the transportation of EKG equipment by portable x-ray suppliers or any other entity.

Below are the definitions for each modifier that must be reported with R0075. Only one of these five modifiers shall be reported with R0075. NOTE: If only one patient is served, R0070 should be reported with no modifier since the descriptor for this code reflects only one patient seen.

UN - Two patients served
UP - Three patients served
UQ - Four patients served
UR - Five Patients served
US - Six or more patients served

Payment for the above modifiers must be consistent with the definition of the modifiers. Therefore, for R0075 reported with modifiers, -UN, -UP, -UQ, and –UR, the total payment for the service shall be divided by 2, 3, 4, and 5 respectively. For modifier –US, the total payment for the service shall be divided by 6 regardless of the number of patients served. For example, if 8 patients were served, R0075 would be reported with modifier –US and the total payment for this service would be divided by 6.

The units field for R0075 shall always be reported as “1” except in extremely unusual cases. The number in the units field should be completed in accordance with the provisions of 100-04, chapter 23, section 10.2 item 24 G which defines the units field as the number of times the patient has received the itemized service during the dates listed in the from/to field. The units field must never be used to report the number of patients served during a single trip. Specifically, the units field must reflect the number of services that the specific beneficiary received, not the number of services received by other beneficiaries.

As a carrier priced service, carriers must initially determine a payment rate for portable x-ray transportation services that is associated with the cost of providing the service. In order to determine an appropriate cost, the carrier should, at a minimum, cost out the vehicle, vehicle modifications, gasoline and the staff time involved in only the transportation for a portable x-ray service. A review of the pricing of this service should be done every five years.

Direct costs related to the vehicle carrying the x-ray machine are fully allocable to determining the payment rate. This includes the cost of the vehicle using a recognized depreciation method, the salary and fringe benefits associated with the staff who drive the vehicle, the communication equipment used between the vehicle and the home office, the salary and fringe benefits of the staff who determine the vehicles route (this could be proportional of office staff), repairs and maintenance of the vehicle(s), insurance for the vehicle(s), operating expenses for the vehicles and any other reasonable costs associated with this service as determined by the carrier. The carrier will have discretion for allocating indirect costs (those costs that cannot be directly attributed to portable x-ray transportation) between the transportation service and the technical component of the x-ray tests.

Suppliers may send carriers unsolicited cost information. The carrier may use this cost data as a comparison to its carrier priced determination. The data supplied should reflect a year’s worth (either calendar or corporate fiscal) of information. Each provider who submits such data is to be informed that the data is subject to verification and will be used to supplement other information that is used to determine Medicare’s payment rate.

Carriers are required to update the rate on an annual basis using independently determined measures of the cost of providing the service. A number of readily available measures (e.g., ambulance inflation factor, the Medicare economic index) that are used by the Medicare program to adjust payment rates for other types of services may be appropriate to use to update the rate for years that the carrier does not recalibrate the payment. Each carrier has the flexibility to identify the index it will use to update the rate. In addition, the carrier can consider locally identified factors that are measured independently of CMS as an adjunct to the annual adjustment.

NOTE: No transportation charge is payable unless the portable x-ray equipment used was actually transported to the location where the x-ray was taken. For example, carriers do not allow a transportation charge when the x-ray equipment is stored in a nursing home for use as needed. However, a set-up payment (see §90.4, below) is payable in such situations. Further, for services furnished on or after January 1, 1997, carriers may not make separate payment under HCPCS code R0076 for the transportation of EKG equipment by portable x-ray suppliers or any other entity.

Thursday, May 9, 2019

CPT 99453, 99454, 99457, 99451, 99452 - Billing Guidelines

2019 CPT codes offer payment for Digital Medicine

Reflecting the reality that physicians and their staff spend an increasing amount of time engaging with technology to enhance and improve patient care, the 2019 Current Procedural Terminology (CPT®) code set that takes effect Jan. 1 provides health professionals the codes they need to get paid for emerging services.

Among the changes in the 2019 CPT code set are three new remote patient monitoring codes that reflect how health professionals can more effectively and efficiently use technology to connect with their patients at home to gather data for care management and coordination. Specifically:

99453 - Remote monitoring of physiologic parameter(s), (for example, weight, blood pressure, pulse oximetry, respiratory flow rate) initial; setup and patient education on equipment use.

99454 - Device(s) supply with daily recording(s) or programmed alert(s) transmission, each 30 days.

99457 - Remote physiologic monitoring treatment management services, 20 minutes or more of clinical staff/physician/other qualified health care professional time in a calendar month requiring interactive communication with the patient/caregiver during the month.

There also are two new interprofessional internet consultation codes to reflect the increasing importance of using non-verbal communication technology to coordinate patient care between a consulting physician and treating physician. Specifically:

99451 - Interprofessional telephone/internet/electronic health record assessment and management service provided by a consultative physician, including a written report to the patient’s treating/requesting physician or other qualified health care professional, 5 minutes or more of medical consultative time.

99452 - Interprofessional telephone/internet/electronic health record referral service(s) provided by a treating/requesting physician or other qualified health care professional, 30 minutes.

Medicare’s acceptance of the new codes would signal a landmark shift to better support physicians participating in patient population health and care coordination services that can be a significant part of a digital solution for improving the overall quality of medical care.


ADDITIONAL COVERAGE REQUIREMENTS FOR THE USE OF THESE CPT CODES INCLUDE:

• Advance patient consent: practitioners must obtain advanced consent for the service and document in the patient’s record.

• 30-day reporting period: billing limited to once in a 30-day period.

• Use with other services: billing is permitted for the same service period as chronic care management (CCM) (CPT  codes 99487-99490), transitional care management (TCM) (CPT codes 99495-99496), and behavioral health integration  (BHI) (CPT codes 99484, 99492-99494).

• The Medicare program will be issuing additional guidance on the type of remote patient monitoring technology that  will be permitted under 99454.

• CPT code 99457 and 99091 may not be billed together for same billing period and beneficiary.



Interprofessional Telephone/Internet Consultations - Uhc Guidelines

UnitedHealthcare follows CMS guidelines effective for services rendered on or after January 1, 2019, which  considers interprofessional telephone/Internet assessment and management services reported with CPT codes 99446 - 99449  and  99451 - 99452 eligible for reimbursement
according to the CMS Physician Fee Schedule (PFS).

Digitally Stored Data Services/Remote Physiologic Monitoring

UnitedHealthcare follows CMS guidelines effective for services rendered on or after January 1, 2019, which  considers digitally stored data services or remote physiologic monitoring services reported with CPT codes 99453, 99454, 99457 ,  and 99091  eligible fo r reimbursement accord ing to the CMS Physician Fee Schedule (PFS).


Modernizing Medicare Physician Payment by Recognizing Communication Technology Based Services


CMS is finalizing its  proposals to pay separately for two newly defined physicians’ services  furnished using communication technology:

• Brief commu nication technology -based service, for example,  virtual check -in  (Healthcare Common Procedure  Coding System (HCPCS) code G2012)

• Remote evaluation of recorded video and/or images submitted by an established patient  (HCPCS code G2010) 

CMS is also finalizing policies to pay separately for new coding describing chronic care remote  physiologic monitoring (Current Procedural Terminology  ( CPT )  codes 99453, 99454, and MLN Matters  99457) and interprofessional internet consultation (CPT codes 99451, 99452, 99446, 99447,  99448 , and 99449).




CY2019 PFS: CPT 99446, 99447, 99449, 99451, 99452


• Interprofessional internet consultation (telephone/internet/electronic health  record)


– CPT 99451  - Assessment and management service provided by a  consultative physician  (WRVU 0.70)

• 5 or more minutes of medical consultative time



CPT 99452  - Referral service(s) provided by a treating/requesting  physician or qualified health care professional  (WRVU 0.70)
• 30 minutes
• Includes a verbal and written report to the patient's treating/requesting physician or other qualified health care professional
• Billing limited to practitioners that can independently bill Medicare for E/M  services


Thursday, April 11, 2019

CPT 0028u, 0029U, 0031U, 0069U, 0070U - 0076U, 81225- 81231

Coding   Code Description CPT

0028U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, copy number variants, common variants with reflex to targeted sequence analysis (new code effective 1/1/18)

0029U Drug metabolism (adverse drug reactions and drug response), targeted sequence analysis (ie, CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, CYP4F2, SLCO1B1, VKORC1 and rs12777823) (new code effective 1/1/18)

0031U CYP1A2 (cytochrome P450 family 1, subfamily A, member 2)(eg, drug metabolism) gene analysis, common variants (ie, *1F, *1K, *6, *7) (new code effective 1/1/18)

0069U Oncology (colorectal), microrna, rt-pcr expression profiling of mir-31-3p, formalin-

0070U fixed paraffin-embedded tissue, algorithm reported as an expression score
CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, common and select rare variants (ie, *2, *3, *4, *4N, *5, *6, *7, *8, *9, *10, *11, *12, *13, *14A, *14B, *15, *17, *29, *35, *36, *41, *57, *61, *63, *68, *83, *xN)
0071U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, full gene sequence (List separately in addition to code for primary procedure)

0072U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, targeted sequence analysis (ie, CYP2D6-2D7 hybrid gene) (List separately in addition to code for primary procedure)

0073U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, targeted sequence analysis (ie, CYP2D7-2D6 hybrid gene) (List separately in addition to code for primary procedure)

0074U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, targeted sequence analysis (ie, non-duplicated gene when duplication/multiplication is trans) (List separately in addition to code for primary procedure)

0075U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, targeted sequence analysis (ie, 5’ gene duplication/multiplication) (List separately in addition to code for primary procedure)

0076U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, targeted sequence analysis (ie, 3’ gene duplication/ multiplication) (List separately in addition to code for primary procedure)

81225 CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (eg, drug


81226 CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN)

81227 CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *5, *6)

81230 CYP3A4 (cytochrome P450 family 3 subfamily A member 4) (eg, drug metabolism), gene analysis, common variant(s) (eg, *2, *22) (new code effective 1/1/18)

81231 CYP3A5 (cytochrome P450 family 3 subfamily A member 5) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *5, *6, *7) (new code effective 1/1/18)

81402 Molecular pathology procedure, Level 3 (eg, >10 SNPs, 2-10 methylated variants, or 210 somatic variants [typically using non-sequencing target variant analysis], immunoglobulin and T-cell receptor gene rearrangements, duplication/deletion variants of 1 exon, loss of heterozygosity [LOH], uniparental disomy [UPD]) includes:




Cytochrome P450 Genotype-Guided Treatment Strategy


Introduction


Metabolism is the term for how the body processes substances. Just as the body processes (metabolizes) foods, it also metabolizes medications. One gene in particular, cytochrome P450 (also called CYP450), is known to be involved in processing a large number of drugs. Certain changes, called mutations, may affect how well or poorly a drug is metabolized. Medical studies have shown that genetic testing for certain CYP450 gene mutations is helpful in determining how a person would metabolize some drugs. For example, drugs like clopidogrel for heart disease, eliglustat for Gaucher disease, and tetrabenazine for Huntington disease. However, reliable and large studies have not yet shown that this type of genetic testing is useful for other drugs. This policy describes when CYP450 genetic testing is covered.



Policy Coverage Criteria 

Test Medical Necessity
CYP450 genotyping (including CYP2C19 and CYP2D6 genes)

CYP450 genotyping for the CYP2C19 gene may be considered medically necessary for the following indication: * To aid in the choice of clopidogrel (Plavix®) versus alternative
anti-platelet agents OR * To determine optimal dosing for clopidogrel  CYP2D6 genotyping to determine drug metabolizer status may be considered medically necessary for the following indications: * Patient with Gaucher disease considering treatment with
eliglustat (Cerdelga™) OR * Patient with Huntington disease considering treatment with
tetrabenazine (Xenazine®) in a dosage greater than 50 mg per day
Test Investigational
CYP450 genotyping (including CYP2C19 and CYP2D6 genes)

CYP450 genotyping (including CYP2C19 and CYP2D6 genes)to determine drug choice or dose for all other drugs not listed in the Medical Necessity section above is considered investigational, unless noted otherwise in a  separate policy (see Related Medical Policies).  The use of genetic testing panels that include multiple CYP450 variants/mutations/polymorphisms is considered investigational. 
Note: Multigene testing panels that include CYP450 and other non CYP450 genes are addressed in other policies. (See Related Medical Policies) This policy only addresses individual genetic tests for CYP450 (including CYP2C19, and CYP2D6 genes).


Related Information 

Definition of Terms

Cytochrome P450: This refers to a family of 60 different enzymes involved in drug and toxin metabolism.
Genotype testing: This is a type of testing used to determine the DNA sequence in genes.
Metabolize: This is a term that refers to breaking down a molecule into smaller units. If a drug is metabolized, it is no longer clinically active.
Polymorphisms: This is a genetic variation between individuals resulting in differences in form or gene expression, in this case differing activity of various enzymes.

Genetics Nomenclature Update 

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics (see Table 1). The Society’s nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.
The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology*“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”*to describe variants identified that cause Mendelian disorders.


Previous  Updated  Definition

variant
Variant Change in the DNA sequence 
Familial variant Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives

Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification Definition
Pathogenic Disease-causing change in the DNA sequence
Likely pathogenic Likely disease-causing change in the DNA sequence 
Variant of uncertain significance Change in DNA sequence with uncertain effects on disease
Likely benign Likely benign change in the DNA sequence
Benign Benign change in the DNA sequence
ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

Genetic Counseling

Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.


Description

The cytochrome P450 (CYP450) family is involved in the metabolism of many currently administered drugs, and genetic variants in cytochrome P450 are associated with altered metabolism of many drugs. Testing for cytochrome P450 variants may assist in selecting and dosing drugs affected by these genetic variants.

Background  Drug Efficacy and Toxicity 

Drug efficacy and toxicity vary substantially between individuals. Because drugs and doses are typically adjusted, if needed, by trial-and-error, clinical consequences may include a prolonged time to optimal therapy. In some cases, serious adverse events may result.
Multiple factors may influence the variability of drug effects, including age, liver function, concomitant diseases, nutrition, smoking, and drug-drug interactions.
Inherited (germline) DNA sequence variation in genes coding for drug-metabolizing enzymes, drug receptors, drug transporters, and molecules involved in signal transduction pathways also may have major effects on the activity of those molecules and thus on the efficacy or toxicity of a drug.

Pharmacogenomics studies how an individual’s genetic inheritance affects the body’s response to drugs. It may be possible to predict therapeutic failures or severe adverse drug reactions in individual patients by testing for important DNA variants (genotyping) in genes related to the metabolic pathway (pharmacokinetics) or signal transduction pathway (pharmacodynamics) of the drug. Potentially, test results could be used to optimize drug choice and/or dose for more effective therapy, avoid serious adverse events, and decrease medical costs.

Cytochrome P450 System

The cytochrome P450 (CYP450) family is a major subset of all drug-metabolizing enzymes; several CYP450 enzymes are involved in the metabolism of a significant proportion of currently administered drugs. CYP2D6 metabolizes approximately 25% of all clinically used medications (eg, dextromethorphan, ß-blockers, antiarrhythmics, antidepressants, morphine derivatives), including most prescribed drugs. CYP2C19 metabolizes several important types of drugs, including proton pump inhibitors, diazepam, propranolol, imipramine, amitriptyline, and clopidogrel.

Some CYP450 enzymes are highly polymorphic, resulting in some enzyme variants that have variable metabolic capacities among individuals, and some with little to no impact on activity. Thus, CYP450 enzymes constitute an important group of drug-gene interactions influencing the variability of the effect of some CYP450-metabolized drugs.

Individuals with 2 copies (alleles) of the most common (wild-type) DNA sequence of a particular CYP450 enzyme gene resulting in an active molecule are termed extensive metabolizers (EMs; normal). Poor metabolizers (PMs) lack active enzyme gene alleles, and intermediate metabolizers, who have 1 active and 1 inactive enzyme gene allele, may experience to a lesser degree some of the consequences of PMs. Ultrarapid metabolizers (UMs) are individuals with more than 2 alleles of an active enzyme gene. There is pronounced ethnic variability in the population distribution of metabolizer types for a given CYP enzyme.

UMs administered an active drug may not reach therapeutic concentrations at usual recommended doses of active drugs, while PMs may suffer more adverse events at usual doses due to reduced metabolism and increased concentrations. Conversely, for administered prodrugs that must be converted by CYP450 enzymes into active metabolites, UMs may suffer adverse events, and PMs may not respond.

Many drugs are metabolized to varying degrees by more than 1 enzyme, either within or outside of the CYP450 superfamily. Also, the interaction between different metabolizing genes, the interaction between genes and environment, and interactions among different nongenetic factors also influence CYP450-specific metabolizing functions. Thus, identification of a variant in a single gene in the metabolic pathway may be insufficient in all but a small proportion of drugs to explain interindividual differences in metabolism and consequent efficacy or toxicity.

Determining Genetic Variability In Drug Response

Genetically determined variability in drug response has been traditionally addressed using a trial-and-error approach to prescribing and dosing, along with therapeutic drug monitoring for drugs with a very narrow therapeutic range and/or potentially serious adverse events outside that range. However, therapeutic drug monitoring is not available for all drugs of interest, and a cautious trial-and-error approach can lengthen the time to achieving an effective dose.

CYP450 enzyme phenotyping (identifying metabolizer status) can be accomplished by administering a test enzyme substrate to a patient and monitoring parent substrate and metabolite concentrations over time (eg, in urine). However, testing and interpretation are timeconsuming and inconvenient; as a result, phenotyping is seldom performed.


The clinical utility of CYP450 genotyping (ie, the likelihood that genotyping will significantly improve drug choice, dosing, and patient outcomes) may be favored when the drug under consideration has a narrow therapeutic dose range, when the consequences of treatment failure are severe, and/or when serious adverse reactions are more likely in patients with gene sequence variants. Under these circumstances, genotyping may direct early selection of the most effective drug or dose, and/or avoid drugs or doses likely to cause toxicity. For example, warfarin, some neuroleptics, and tricyclic antidepressants have narrow therapeutic windows and can cause serious adverse events when concentrations exceed certain limits, resulting in cautious dosing protocols. The potential severity of the disease condition may call for immediate and sufficient therapy; genotyping might speed up the process of achieving a therapeutic dose and avoiding significant adverse events.FDA has required the package insert for clopidogrel carry a black box warning concerning possible worse outcomes with clopidogrel treatment in patients with genetic variants. The FDA warning suggests changes in doses or changes in drug.



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