Genomics
October 2025 - CYP2C19 position statement
NICE have recently published guidance regarding the use of CYP2C19 genotype testing and CYP2C19 metaboliser status in guiding prescription of Clopidogrel in the setting of acute Stroke and TIA. The RCGP have worked with stakeholders to produce information to support prescribers outside of the acute Stroke setting who receive information that a patient has had CYP2C19 genotype testing.
CYP2C19 Genotyping Implementation Position Statement (PDF file, 295 KB)
October 2025 - Updated guidance on Direct to Consumer (DTC) genomic or genetic testing
Since 2019 Companies that offer DTC-GT are expanding their activities in the UK and globally1. In 2025 The Royal College of General Practitioners (RCGP) in collaboration1 with partners and stakeholders have updated the guidance with the following key recommendations:
- Healthcare professionals should not take at face value, or attempt to interpret, reports from non-accredited laboratories or third-party interpretation services.
- Patients presenting with DTC-GT results to healthcare professionals should be offered the same NHS care as those who have not had DTC-GT.
- DTC-GT results should not affect access to treatment(s) that are not commissioned for that indication within the NHS.
2025 Guidance
These recommendations are relevant to medicines optimisation, to all prescribers and roles involved in medicines review including stroke teams, primary care prescribers, pharmacists, clinical pharmacologists and prescribers in medical and care of the elderly settings.
The National Institute for Health and Care Excellence (NICE) guidance recommends use of CYP2C19 testing to guide new prescription of clopidogrel in acute ischaemic stroke or transient ischaemic attack and the Medicines and Healthcare products Regulatory Agency (MHRA) requires CYP2C19 genotype for mavacamten use in the treatment of hypertrophic obstructive cardiomyopathy. Clinical teams requesting CYP2C19 testing have a responsibility to communicate prescribing actions to the patient and to communicate relevant data across the healthcare system.
- Diagnostics Guidance [DG59]: CYP2C19 testing to guide clopidogrel use after ischaemic stroke or transient ischaemic attack (TIA) (July 2024).
- Technology appraisal guidance [TA913]: Mavacamten for treating symptomatic hypertrophic obstructive cardiomyopathy (December 2023).
Recommendation 1:
Structured data capturing CYP2C19 metaboliser status should be included in the patient record and related communications. The following SNOMED-CT codes should be utilised:
- Cytochrome P450 family 2 subfamily C member 19 poor metaboliser (finding) SCTID: 738786005
- Cytochrome P450 family 2 subfamily C member 19 intermediate metaboliser (finding) SCTID: 738787001
- ytochrome P450 family 2 subfamily C member 19 normal metaboliser (finding) SCTID: 738788006
- Cytochrome P450 family 2 subfamily C member 19 rapid metaboliser (finding) SCTID: 787193001
- Cytochrome P450 family 2 subfamily C member 19 ultra-rapid metaboliser (finding) SCTID: 738790007
Use of CYP2C19 metaboliser status to guide prescription of other medications, changes to pre-existing clopidogrel prescription and clopidogrel prescription for other indications is not addressed in current UK guidance and is outside the scope of current routine NHS practice.
Recommendation 2:
With the exception of prescription initiation in the context of acute ischaemic stroke, transient ischaemic, or Obstructive Hypertrophic Cardiomyopathy (Mavacamten) prescribers should not be expected to utilise CYP2C19 metaboliser status to guide prescribing practice until the following are implemented within NHS infrastructure:
- UK-based guidance which supports genomics-informed medicines optimisation
- Clinical Decision Support Systems which present CYP2C19 metaboliser status and integrate with UK-based guidance to provide evidence-based actionable recommendations at point-of-prescription
- Competency frameworks and educational resources supporting core knowledge and skills for prescribers.
Prescribers with additional expertise in Genomics-informed Medicines optimisation may wish to utilise CYP2C19 metaboliser status to guide prescribing decisions pending the publication of UK guidance.
Recommendation 3:
Prescribers should:
- always act within the limits of their knowledge and competency to ensure they provide ‘reasonable care’, and seek advice from expert sources if needed
- act in the context of shared decision-making with the patient.
- reference and take into account trusted UK sources such as MHRA Drug Safety alerts, Summary of Product Characteristics (SmPC), the BNF, local and national guidance
- Follow appropriate local procedures for non-formulary, off-label, or unlicensed medication use.
2.1 Pharmacogenomics
Pharmacogenomics refers to the use of genomic information to predict effectiveness or the risk of an adverse drug reaction (ADR) to a particular medication: genomics-informed medicines optimisation describes its use to guide prescribing decisions. It has the potential to significantly improve patient outcomes to certain medications and has been implemented for specific drug-gene pairs. Its use is predicted to increase significantly over coming years as evidence of utility increases and processes to support its use are developed.
Testing for variants in the CYP2C19 gene can help predict the response to several medicines metabolised by the CYP2C19 liver enzyme encoded by this gene. The genotype directly affects the level of enzyme function, referred to as ‘metaboliser status’ of which there are 5 types listed in Table 1.
- Poor Metabolisers (PM): These individuals are predicted to have reduced enzyme function.
- Intermediate Metabolisers (IM): These individuals are predicted to have a moderate level of enzyme function.
- Extensive or Normal Metabolisers (EM): These individuals are predicted to metabolise drugs at a normal rate, which is considered the standard or typical response.
- Rapid Metabolisers (RM): These individuals are predicted to metabolise drugs at an increased rate.
- Ultra-rapid Metabolisers (UM): These individuals are predicted to metabolise drugs rapidly.
An individual’s genotype result is just one factor which influences response to medicines, in combination with other factors such as age, renal function, comorbidities and other medicines. As such, an individual’s pharmacogenetic results should always be considered holistically.
2.2 Data and Informatics considerations
NICE have issued two sets of guidance regarding CYP2C19 “genotype-guided” prescribing in the UK, which will result in the generation of CYP2C19 metaboliser status within Inherited Cardiac Conditions and Acute Stroke healthcare settings respectively:
- Technology appraisal guidance [TA913]: Mavacamten for treating symptomatic hypertrophic obstructive cardiomyopathy (December 2023). Overview | Mavacamten for treating symptomatic obstructive hypertrophic cardiomyopathy | Guidance | NICE
- Diagnostics Guidance [DG59]: CYP2C19 genotype testing to guide clopidogrel use after ischaemic stroke or transient ischaemic attack (TIA) (July 2024). Overview | CYP2C19 genotype testing to guide clopidogrel use after ischaemic stroke or transient ischaemic attack | Guidance | NICE
The Professional Record Standards Body (PRSB) ‘Guidance for using pharmacogenomic information in clinical practice’ includes recommendations that genetic data should be: recorded in standardised terminology and formats in electronic health records (EHRs), integrated with clinical decision support in the form of evidence-based actionable recommendations at the point of prescribing, available for patients and interoperable to allow sharing of information across the healthcare system.
Accurate recording and availability of CYP2C19 metaboliser status within the health record is crucial to ensure that the rationale for CYP2C19-guided prescription of Clopidogrel for an individual patient is clear and not reversed during subsequent healthcare contacts and medication reviews. NHSE-convened Pharmacogenomics Digital Group has recommended recording of structured data in the form of SNOMED-CT codes for CYP2C19 metaboliser status. This also supports patient access and availability for future prescribing decisions in line with developing UK guidance.
2.3 CYP2C19 metaboliser status additional implications
CYP2C19 metaboliser status is relevant to prescription of clopidogrel for additional indications;2C19 individuals who are poor or intermediate metabolisers are predicted to derive less benefit from clopidogrel when prescribed in the context of ischaemic heart disease and peripheral vascular disease. CYP2C19 metaboliser status is also relevant to prescription of other medications including Selective Serotonin Re-uptake Inhibitors (SSRIs) and Proton Pump Inhibitors (PPIs), with implications for risk of adverse events and likely medication effectiveness.
Individuals who are CYP2C19 poor metabolisers are at increased risk of side-effects from SSRIs, most notably prolonged QT-interval with citalopram. In the UK for citalopram the SmPC states that “ An initial dose of 10 mg daily during the first two weeks of treatment is recommended for patients who are known to be poor metabolisers with respect to CYP2C19. The dose may be increased to a maximum of 20 mg daily.”
2.4 Prescriber responsibilities and legal issues. Guidance and Resources
The RCGP Curriculum states “it is essential to follow the law and GMC guidance and to take account of licensing and local prescribing guidance as well as other relevant regulations. This includes clinical guidelines published by”:
- NICE (England) | NICE
- SIGN (Scotland)
- Scottish Medicines Consortium and Health Improvement Scotland (Scotland) SMC | Scottish Medicines Consortium
- Department for Health, Social Services and Public Safety (Northern Ireland) Department of Health
- All-Wales Medicines Strategy Group (Wales) All Wales Medicines Strategy Group | GOV.WALES
- Medical Royal Colleges and other authoritative sources AOMRC
- The British National Formulary (BNF) BNF (British National Formulary) | NICE
- BNF for Children BNFC (British National Formulary for Children) | NICE
As of January 2025 there is no other peer-reviewed UK guidance (outside that listed in section 2.4 or standards for clinical practice relevant to CYP2C19 testing or metaboliser status.
International clinical guidelines developed by the Clinical Pharmacogenetics Implementation Consortium (CPIC) summarise the evidence base and prescribing recommendations for genomics-informed medicines optimisation of medications impacted by CYP2C19 metaboliser status and of Clopidogrel for alternative indications.
3.0 Conclusions
Patients within England will be eligible for CYP2C19 testing for specified indications: new Clopidogrel prescription for acute stroke and TIA, and Mavacemten for Hypertrophic Cardiomyopathy. This will result in a scenario where CYP2C19 metaboliser status will be generated in the absence of implemented informatics solutions and data standards to support sharing of the data across care settings, the absence of UK clinical guidance for use outside of these indications and the absence of a clinical decision support system which integrates with evidence-based actionable prescribing recommendations.
Several national programmes and workstreams are working to generate evidence and consensus to address these gaps in implementation including NHS England and the national PROGRESS pilot study (Spotlight: PROGRESS project: North West Genomics Medicine Service Alliance) This position statement provides interim support and recommendations for prescribers until these implementation gaps are addressed.
4.0 Genomics-informed medicines optimisation: The Future
Several national programmes are underway to support prescribers in implementing pharmacogenomics over the medium to long term, including:
- NHSE collaboration with the BNF
- PROGRESS / Clinical Decision Support Systems (CDSS)
- Workforce development and educational initiatives, including a competency framework (NHSE Genomics Education Programme) and ‘just in time’ resources (GeNotes)
- Centre for Excellence in Regulatory Science and Innovation in Pharmacogenomics.
5.0 References and Supporting resources
Includes here table of metaboliser statuses and frequencies for different ethnicities
Clopidogrel - Knowledge Hub Includes metaboliser statuses
Academy of Medical Sciences. 24207767
Spotlight: PROGRESS project: North West Genomics Medicine Service Alliance
NHS England » National genomic test directory
The Professional Record Standards Body - PRSB
Clinical Pharmacogenetics Implementation Consortium CPIC
Patient Information
6.0 Authorship
Lead Authors: Dr. Jude Hayward, Dr. Imran Rafi, Professor Anthony Avery
Chair of the UK Pharmacogenetics & Stratified Medicine Network (UKPGx), Professor Sir Munir Pirmohamed
Members of the working group:Includes members of the NHSE Network of Excellence in Pharmacogenomics and Medicines Optimisation, Clinical Genetics, NHS Genomics Unit, Academia, Informatics and General Practice.
- Prof Bill Newman, Clinical Director NHSE Network of Excellence in Pharmacogenomics and Medicines Optimisation
- Professor Tony Avery
- Dr. Michael Clark
- Vicky Chaplin
- Jessica Keen
- Anthony Sutcliffe
- Dr. Imran Rafi
- Dr. Emma Magavern
- Claire Vaughan
- Dr. John McDermott
- Dr. Videha Sharma
- Charlotte Skitterall
- Dr. Rhys Beynon
- Dr. Julia Darko
October 2019
The Royal College of General Practitioners (RCGP) and the British Society for Genetic Medicine (BSGM) recommended that healthcare professionals should exercise caution when asked to offer, or provide, clinical expertise about the results of Direct to Consumer (DTC) genomic or genetic testing.
The analytical validity, sensitivity and clinical utility of such testing may have been much lower than is popularly perceived. It was considered that for certain types of DTC results, there was a very high chance of false positive or false negative results which means that patients should be offered the NHS care which would otherwise have been offered (e.g., family history and risk assessment, healthy lifestyle advice, or referral to specialist care)1 regardless of their DTC result.
Reference:
- British Society for Genetic Medicine, Royal College of General Practitioners, Royal Pharmaceutical Society, British Pharmacological Society, UK Clinical Pharmacy Association. Direct-to-consumer genomic testing: Position statement. September 2025. London: BSGM, 2025.
2019 Guidance
Companies that offer Direct to Consumer (DTC) genetic/genomic testing are increasing their marketing activities in the UK and over the internet and are targeting healthy people. The technology to analyse a person’s [heritable] DNA (genetic code) is now fast and cheap. Exemplar types of test results from direct-to-consumer testing include:
- Gene variants giving information regarding single gene conditions or predispositions: examples may be variants in breast cancer related genes (BRCA1 or BRCA2), or the Cystic Fibrosis gene (CFTR). Results may be:
- False negatives: The genes may have many different types of variation within them, yet often DTC testing only looks for a small proportion. Thus testing will miss a large proportion of these, for example in the region of 80% of known BRCA1/2 mutations are missed by commercial companies who generally only analyse three of the many different possible mutations.
- False positives: DTC tests that use a “SNP chip” [single nucleotide polymorphism] technique [used by the majority of companies in operation in 2019] are very likely to categorise rare variants wrongly2. Thus 85-95% of BRCA1/2 variants or Bowel cancer gene variants for example, will be false positives or artefacts. The impact of false positives will likely place increasing demand on the health service which will need to spend considerable time and money counselling patients and reanalysing their samples.
- Combination of genes which indicate susceptibility to a common complex or multifactorial condition e.g. Parkinson’s disease or diabetes. For these conditions there may be a combination of gene variants which individually have small effects, but in combination have additive effects that increase susceptibility to a common complex condition. These tests may have similar issues in relation to false negatives and positives as outlined above. Their predictive value (or reassurance value) even where true positive or negative may be poor.
- Pharmacogenomic variants: gene variants which affect an individual’s response to a medication, giving information predicting effectiveness of the medication or predicting an adverse drug reaction (or a suboptimal response). These tests have similar issues in relation to false negatives and positives as outlined above.
NHS patients may present to their GP or other NHS professionals requesting help with the interpretation of DTC genomic results. Care should be taken not to take these results at face value.
The ability to confidently interpret how variation within the genetic code impacts a person’s health or risk of disease is often weaker than people expect. Furthermore it will often require contextual information such as clinical signs, symptoms or family history to facilitate interpretation. Within the NHS, the Genomics Test Directory lists which genetic tests accredited laboratories3 can provide if particular criteria (e.g. clinical context) are met. Confirming a clinical diagnosis through genomic testing can be very helpful, however predicting future health problems from genomic testing alone is still a vague inaccurate science. This fact can come as a surprise to patients and professionals since the discourse about genomics is often rather deterministic.
Patients should not be referred to secondary or tertiary care solely on the basis of DTC results alone. Because of the high chance of false positive or false negative results, referrals are only indicated if existing referral criteria are met.
Referral should be considered if a variant is found in a gene for which testing is offered on the NHS, or if both members of a couple are found to be carriers for a genetic condition. Referral should also be based on clinical signs, symptoms, or family history of disease. Genomic services are generally able to provide advice where it is not clear whether a particular patient meets these referral criteria.
- GPs should not take at face value, or attempt to interpret, reports from non-accredited and non-kite-marked laboratories such as DTC companies.
- GPs should use clinical and family history to assess the chance of heritable disease. Where a patient has a medical history or family history which suggests that genomic testing is indicated, then they should be referred via appropriate pathways regardless of their DTC test results.
- If a patient who has had a DTC test is reported to have an alteration in a gene for which NHS testing is offered (e.g. BRCA) then you should discuss with your regional NHS genetics clinic whether referral is appropriate. Please note that majority of these results will be artefacts due to the technology used.
- If a patient wants to discuss a DTC result for which NHS genomic testing is not usually offered (e.g. paternity tests or ancestry information) then they should be signposted to the commercial DTC provider. Such predictions rarely have health implications and therefore do not fall under the auspices of the NHS.
- We support educational campaigns (DH, HEE) informing patients of the limitations of DTC testing, and recommending that regulators should be asking that DTC testing companies provide clinical support as part of the models informing patients of the limitations of DTC testing.
In order to provide high quality, cost-efficient care in the NHS, it is important to note that many DTC results done without clinical indications may be wrong. There are significant NHS costs in confirming (or more often refuting) DTC testing results and these are not warranted unless there are clinical indications for testing.
Patients presenting with DTC results to their GP should be offered usual NHS care: family history and risk assessment, with onward referral and testing as per standard NHS pathways and protocols.
- Horton R et al. Direct-to-consumer genetic testing. BMJ 2019; 367
- Weedon MN et al. Very rare pathogenic genetic variants detected by SNP-chips are usually false positives: implications for direct-to-consumer genetic testing. BioRxiv 696799
- NHS England and Improvement. National Genomic Test Directory. 2018.
Dr Imran Rafi, Dr Judith Hayward and Professor Anneke Lucassen
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