Rare Disease 1 —
Training activity: 3

Details

Review referrals; analyse, interpret, and report results for Next Generation Sequencing (NGS) panels for patients referred for investigation of rare disease using HGVS nomenclature to describe genomic sequence changes.

Type

Entrustable training activity (ETA)

Evidence requirements

Evidence the activity has been undertaken by the trainee repeatedly, consistently, and effectively over time, in a range of situations. This may include occasions where the trainee has not successfully achieved the outcome of the activity themselves. For example, because it was not appropriate to undertake the task in the circumstances or the trainees recognised their own limitations and sought help or advice to ensure the activity reached an appropriate conclusion. ​

Reflection at multiple timepoints on the trainee learning journey for this activity.

Reflective practice guidance

The guidance below is provided to support reflection at different time points, providing you with questions to aid you to reflect for this training activity. They are provided for guidance and should not be considered as a mandatory checklist. Trainees should not be expected to provide answers to each of the guidance questions listed.

Before action

What does success look like?

• How will you identify what is expected of you in relation to accurately analysing, interpreting, and reporting results for rare disease NGS panels using HGVS nomenclature?
• In what ways will you demonstrate effective triaging to ensure the selected NGS panel is appropriate for the patient’s clinical presentation?
• How will you evaluate the quality control (QC) metrics of the NGS run to ensure the data is robust enough for a diagnostic report?
• What constitutes a high-quality report that accurately uses HGVS nomenclature to describe variants and identifies their clinical significance?
• How will you gain clarity on the expected depth of interpretation and the local standards for reporting rare disease findings?

What is your prior experience of this activity?

• What is your current understanding of the principles of the NGS assay used in your laboratory, and what previous experience can you draw upon regarding similar bioinformatics pipelines or variant interpretation tasks?
• What specific challenges do you anticipate facing, such as managing low coverage in critical regions, filtering high volumes of data, or applying ACGS/ACMG best practice guidance to complex sequence changes?
• How will you recognise the scope of your own practice for this activity, and in what situations—such as encountering a complex structural variant or a finding with significant familial implications—will you seek advice from a senior clinical scientist?
• How would you describe your current feelings regarding embarking on this analysis, particularly concerning the professional responsibility of reporting results for rare disease patients?

What do you anticipate you will learn from the experience?

• Which specific skills do you want to develop, such as proficiency in using bioinformatic tools for variant prioritisation or mastering the nuances of HGVS nomenclature for complex indels?
• What specific insights do you hope to gain regarding the correlation between the rare disease phenotype and the variants identified within the panel?
• In what ways do you expect this activity to improve your understanding of how QC metrics (e.g., Q-scores or depth) influence clinical confidence in a result?

What additional considerations do you need to make?

• How will you consult actions identified following previous experiences of variant interpretation or report writing to ensure you apply that feedback to these cases?
• Which specific information sources—including National Genomic Test Directory entries, the technical principles of the NGS assay, and current best practice guidelines—must you review before starting to ensure your approach is evidence-based and safe?
• How will you review the limitations of current assay methodologies to ensure your recommendations for further testing are both technically feasible and clinically appropriate?

In action

During the activity, did anything unexpected occur?

• What aspects of the NGS data processing are you noticing that are surprising or different from your initial plan?
• How are you managing novel or complex variants (e.g. indels or splice sites) that require immediate reference to external guidelines or databases?
• In what ways are you navigating technical limitations, such as low coverage, that complicate variant calling and interpretation?
• How are you adjudicating conflicting evidence (e.g. ClinVar vs. HGMD) for identified variants?
• How are you addressing findings that do not align with the clinical presentation or reported rare disease phenotype?
• How are you distinguishing true sequence changes from data quality issues or artifacts in the alignment data?

How are you reacting to the unexpected development?

• How is this unexpected development impacting your actions in the moment, and are you adapting your filtering or analysis approach appropriately?
• How are you reviewing raw sequencing or alignment data to verify the quality and validity of challenging variant calls?
• Which best practice guidelines (e.g. ACGS or ACMG) or testing algorithms are you consulting to resolve interpretative ambiguity?
• How are you identifying the specific point where you must seek immediate advice from a senior specialist regarding novel or complex findings?
• How are you feeling in that moment? Is the complexity of the HGVS nomenclature or the variant spectrum affecting your confidence in reaching a successful diagnostic conclusion?

What was the conclusion or outcome?

• How are you ensuring you are working within your scope of practice, and at what point did you identify that the case complexity required senior support?
• What are you learning in real-time as a result of the unexpected development, such as mastering a more effective filtering strategy for high-volume data or gaining insight into QC metrics like coverage and Q-scores?
• In what ways are you ensuring that your real-time decisions and final report consider the potential implications of the findings for the patient and their wider family?

On action

What happened?

• Summarise the key points of the experience, detailing the specific rare disease NGS panels you reviewed and the process of analysing the results.
• Describe the essential technical or clinical details that felt important, such as reviewing complex clinical presentations to triage referrals or evaluating quality control (QC) metrics (e.g., depth of coverage, Q-scores) to ensure data integrity.
• Include any ‘reflect-in-action’ moments where you had to adapt. For instance, did you have to adjust your filtering parameters based on limited clinical information or re-evaluate a variant due to conflicting database entries?
• How did you feel during the process? Did you feel confident using HGVS nomenclature to describe sequence changes, or did the complexity of certain variants cause uncertainty?

How has this experience contributed to your developing practice?

• Identify what you learned regarding the application of NGS panels and how interpreting these results informs patient diagnosis and management.
• What strengths did you demonstrate, such as proficiency in variant filtering or a systematic approach to interpreting genomic variants?
• What knowledge gaps were evident? For example, did you face difficulty using specific bioinformatic tools or applying best practice guidelines to novel variants?
• Compare this experience against previous sequencing or analysis activities. Have you achieved previously identified actions for development?
• Identify any challenges (e.g., technical limitations like low coverage or ambiguous nomenclature) and how you reacted to them. Did you need to seek advice or escalate the case to a senior clinical scientist to stay within your scope of practice?

What will you take from the experience moving forward?

• Identify the actions you will now take to support the assimilation of what you have learned, including any feedback received.
• What will you do differently next time you analyse and interpret NGS panel data? For instance, will you change how you cross-reference clinical features with variant lists?
• Do you need to practice any aspect of the activity further, such as undertaking additional training in specific bioinformatics approaches or mastering the reporting of specific complex variant types (e.g., large indels)?
• How will you ensure you stay up to date with evolving HGVS nomenclature and best practice interpretation guidelines for rare disease genomics?

Beyond action

Have you revisited the experiences?

• Have you reviewed your triage decisions and report drafts from earlier reflections?
• Identify specific actions you previously noted were needed to improve your practice—such as mastering a specific bioinformatic tool, refining your use of HGVS nomenclature, or improving your assessment of QC metrics like coverage—and determine if you have completed these.
• Are you now ready to demonstrate this new learning in practice for increasingly complex rare disease panels?
• Has discussing challenging variant classifications or technical troubleshooting in multidisciplinary team (MDT) meetings changed your perspective on how to integrate complex data into a clinical report?

How have these experiences impacted upon current practice?

• Consider how the accumulated learning from performing and reflecting on NGS analysis supports you in preparing for observed ‘in-person’ assessments, such as:
• Direct Observation of Practical Skills (DOPS): e.g. ‘Classify a variant’ or ‘Analyse and interpret results for a genetic investigation’.
• Observed Communication Events (OCE): e.g., Providing advice to another professional on sample requirements or reporting results.
• How has your practice developed and evolved over time? For example, can you see a clear improvement in your ability to correlate rare disease phenotypes with genomic findings compared to your initial attempts?
• Are you more confident in recognising when a case is beyond your scope of practice, such as an NGS result that suggests a complex structural variant or mosaicism that requires senior specialist review?
• How has this foundational experience with NGS panels influenced your approach to other datasets, such as applying these analytical principles to Whole Exome (WES) or Whole Genome (WGS) sequencing in the future?

How might these contribute to your future practice?

• What transferable skills—such as clinical reasoning, diagnostic planning, and high-level technical problem-solving—are you developing through this activity?
• As genomic technologies evolve, how will your understanding of assay principles and QC help you evaluate and adopt new genomic technologies or testing algorithms in your future post-programme practice?
• What clear actions for continued development have you identified to ensure you stay current with the evolving landscape of rare disease genomics and bioinformatic pipelines?

Relevant learning outcomes

#	Outcome
# 1	Outcome Triage referrals for rare disease genomic investigations.
# 2	Outcome Perform targeted and chromosomal analysis for patients referred for investigation of rare disease.
# 3	Outcome Interpret genomic variants to investigate the clinical significance using appropriate nomenclature.
# 4	Outcome Interpret and report genomic testing for Next Generation Sequencing (NGS) panels.