RARE-GEN Clinical Masterclass: Advanced Variant Classification and Prioritization in Rare Disease Diagnosis

RARE-GEN Clinical Masterclass: Advanced Variant Classification and Prioritization in Rare Disease Diagnosis
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  • 7-9 December 2025
  • Sidra Medicine

Target Audience

  • Physicians
  • Allied Health Professionals
  • Nurses
  • Others (Scientists and Researchers)

Facilitator/s

  1. Rozaimi Razali (Assistant Professor, Bioinformatician)
  2. Najeeb Syed (Staff Scientist, Bioinformatician)
  3. Aljazi Al Maraghi (Staff Scientist, Bioinformatician)
  4. Shahzad Ahmad (Staff Scientist, Bioinformatician)
  5. Ms. Rulan Shaath (Research Specialist, Bioinformatician)

Overall Learning Objectives

By the end of the RARE-GEN Clinical Masterclass, participants will be able to:

  1. Apply internationally recognized variant interpretation frameworks (e.g., ACMG/AMP guidelines) to classify genetic variants in rare disease diagnostics.
  2. Analyze genomic data using evidence-based tools such as ClinVar, ClinGen, GenCC, and gnomAD to support accurate clinical decision-making.
  3. Evaluate real-world cases and prioritize variants based on gene-disease validity, population frequency, and phenotypic relevance to improve diagnostic outcomes.

 

Program Overview

DAY 1 – 07/12/2025

Time Session Title/Topic Session-Specific Learning Objectives
At the end of this session, participants will be able to:
09:00-10:00 AM
(1 hrs)
ClinGen Overview

Speaker: Erin Riggs

  • Describe the mission, structure, and key components of the Clinical Genome Resource (ClinGen) initiative.
  • Explain how ClinGen supports evidence-based variants and gene curation for rare disease diagnosis.
  • Navigate major ClinGen resources and working group outputs relevant to clinical practice and research.
10:00-11:00 AM
(1 hrs)
Introduction to CLIN Var

Speaker: Steven Harrison

  • Explain the purpose and structure of ClinVar as a publicly available archive of variant interpretations.
  • Identify the types of data submitted to ClinVar and how they are organized and displayed.
  • Demonstrate how to search, interpret, and utilize ClinVar entries for clinical variant assessment.
11:00 – 11:30 AM Coffee Break
11:30 – 12:30 PM
(1 hr)
Gene Curation and Supporting Resources

Speaker: Erin Riggs

  • Describe the ClinGen gene curation framework and its application to evaluating gene-disease validity.
  • Identify key resources and databases that support gene curation efforts, including GenCC and expert panels.
  • Apply gene curation criteria to assess gene-disease associations in the context of rare disease diagnostics.
12:30 – 1:30 PM
(1 hr)
Gene Curation SOP and Curation Examples

Speaker: Erin Riggs

  • Summarize the standard operating procedures (SOPs) used in ClinGen gene curation.
  • Interpret real-world examples of gene-disease curation and how evidence is evaluated and scored.
  • Apply the SOP framework to assess gene-disease validity through guided case-based discussions.
01:30 – 02:30 Lunch Break
2:30 – 3:30 PM
(1 hr)
Group Gene Curation Examples

Speaker: Erin Riggs and Steven Harrison

  • Collaborate effectively in a group setting to perform gene-disease validity curation using established ClinGen frameworks.
  • Evaluate different types of evidence (genetic, experimental, case-level) through real-world gene curation examples.
  • Justify classification decisions based on consensus discussions and ClinGen scoring guidelines.
3:30 – 4:30 PM
(1 hr)
Introduction to GenCC

Speaker: Erin Riggs

  • Describe the purpose and structure of the Gene Curation Coalition (GenCC) and its role in harmonizing gene-disease validity assertions.
  • Identify key contributors, data standards, and tools provided by GenCC to support gene curation.
  • Utilize the GenCC database to explore and compare gene-disease validity classifications across different organizations.
4:30 – 5:30 PM
(1 hr)
Navigating gnomAD

Speaker: Steven Harrison

  • Explain the structure, purpose, and population coverage of the Genome Aggregation Database (gnomAD).
  • Interpret variant frequency data within gnomAD to assess potential pathogenicity in rare disease contexts.
  • Demonstrate how to navigate and extract relevant information from gnomAD using variant- and gene-level queries.

DAY 2 – 08/12/2025

Time Session Title/Topic Session-Specific Learning Objectives
At the end of this session, participants will be able to:
09:00-10:00 AM
(1 hrs)
Variant Curation

Speaker: Steven Harrison

  • Describe the principles and workflow of variant curation based on ACMG/AMP guidelines.
  • Apply standardized criteria to assess variant pathogenicity using clinical and population data.
  • Interpret curated variant evidence in the context of rare disease diagnosis and clinical decision-making.
10:00-11:00 AM
(1 hrs)
ClinGen Variant Specifications

Speaker: Steven Harrison

  • Explain how ClinGen develops gene- and disease-specific specifications of the ACMG/AMP variant interpretation guidelines.
  • Differentiate between general ACMG criteria and expert panel–specified modifications used in variant assessment.
  • Apply ClinGen expert specifications to evaluate variants more accurately within specific gene-disease contexts.
11:00 – 11:30 AM Coffee Break
11:30 – 12:30 PM
(1 hr)
CNV Classification

Speaker: Erin Riggs

  • Describe the ClinGen/ACMG framework for classifying copy number variants (CNVs) in clinical genomics.
  • Evaluate CNVs using evidence categories such as gene content, dosage sensitivity, and population frequency.
  • Apply classification guidelines to real-world CNV examples for diagnostic interpretation in rare disease cases.
12:30 – 1:30 PM
(1 hr)
WGS Analysis and Workflow

Speaker: Steven Harrison

  • Outline the end-to-end workflow of whole genome sequencing (WGS), from raw data generation to variant interpretation.
  • Identify key tools and pipelines used in alignment, variant calling, annotation, and filtering in WGS analysis.
  • Evaluate WGS data in the context of rare disease diagnosis, including detection of SNVs, CNVs, and structural variants.
01:30 – 02:30 Lunch Break
2:30 – 3:30 PM
(1 hr)
Group Variant Curation Examples

Speakers: Erin Riggs and Steven Harrison

  • Collaborate in a team setting to curate genetic variants using ACMG/AMP criteria and ClinGen expert guidance.
  • Apply evidence-based classification frameworks to real case examples through group discussion and consensus-building.
  • Demonstrate practical skills in navigating curation tools and databases (e.g., ClinVar, gnomAD, ClinGen) to support variant interpretation.
3:30 – 4:30 PM
(1 hr)
Case Analysis

Speaker: Steven Harrison

  • Analyze clinical case studies involving rare disease patients using structured genomic interpretation frameworks.
  • Integrate genomic data, family history, and phenotypic details to support accurate variant classification.
  • Formulate evidence-based conclusions and recommendations for diagnosis or further testing through case-based discussion.
4:30 – 5:30 PM
(1 hr)
Patient Registries (GenomeConnect)

Speaker: Erin Riggs

  • Describe the role of GenomeConnect and similar patient registries in bridging genomic research and clinical care.
  • Explain how patient-contributed data can support variant interpretation, data sharing, and reclassification efforts.
  • Evaluate the impact of patient registries on longitudinal data collection, patient engagement, and evidence generation in rare diseases.

DAY 3 – 09/12/2025

Time Session Title/Topic Session-Specific Learning Objectives
At the end of this session, participants will be able to:
09:00-09:30 AM
(0.5 hrs)
Introductory Remarks and The Genetic Counselors role in Variant Interpretation

Speaker: Margaret Harr

Facilitator: Reem Bux

  • Articulate the goals, structure, and expected outcomes of the Genomic Quality Assurance Masterclass within the context of improving diagnostic excellence in genomics.
  • Highlight the clinical and scientific importance of quality assurance, accreditation, and competency assessment in both germline and somatic genomic testing services.
  • Describe how this masterclass addresses current gaps in practice, aligns with international standards, and supports national efforts in improving genomic service delivery.
  • Define the scope and responsibilities of genetic counselors in the process of variant interpretation and communicating genomic results to patients and healthcare teams.
  • Apply ACMG/AMP guidelines and clinical context to support classification and interpretation of variants of uncertain significance (VUS), pathogenic, and benign findings.
  • Evaluate case-based examples where genetic counselor input directly influences variant reclassification, informed consent, and return-of-results discussions.
09:30-11:00 AM
(1.5 hrs)
Open-Access Artificial Intelligence and the Patient Experience workshop

Speaker: Margaret Harr

  • Describe the potential applications of open-access artificial intelligence tools in genomic diagnostics and their influence on clinical workflows and patient engagement.
  • Evaluate the ethical, practical, and data governance considerations surrounding AI-driven tools in patient-facing genomic services, including informed consent and result communication.
  • Assess how AI-enabled decision support systems can improve the patient experience by enhancing the accuracy, timeliness, and personalization of genomic test interpretation.
11:00 – 11:30 AM Coffee Break
11:30 – 12:00 PM
(0.5 hrs)
Introduction to Multidisciplinary Care Clinics

Speaker: Margaret Harr

  • Define the structure and purpose of multidisciplinary care clinics (MDCCs) in the context of genomic medicine, particularly for patients with rare or complex genetic conditions.
  • Describe the roles of various professional clinical geneticists, genetic counselors, laboratory scientists, and specialists—in coordinating care and delivering integrated genomic services.
  • Evaluate the benefits and challenges of implementing MDCCs, including improved diagnostic accuracy, streamlined patient pathways, and enhanced communication between stakeholders.
12:00 – 12:30 PM
(0.5 hrs)
There’s no “I” in TEAM

Speaker: Margaret Harr

  • Recognize the value of interdisciplinary teamwork in delivering high-quality genomic testing services, from sample processing to clinical interpretation and patient communication.
  • Describe the roles and responsibilities of key team members—such as genetic counselors, lab scientists, quality managers, and clinicians—in maintaining quality standards and achieving accreditation.
  • Apply strategies for effective communication, shared accountability, and continuous feedback within genomic teams to support a culture of quality and safety.
01:30 – 02:30 Lunch Break
2:30 – 3:30 PM
(1 hr)
Building an MDC from the ground up

Speaker: Margaret Harr

  • Outline the key components required to establish a successful multidisciplinary clinic (MDC) for genomic and rare disease care, including staffing, infrastructure, and referral pathways.
  • Identify the logistical, regulatory, and operational challenges in launching an MDC, and explore solutions for integrating genomic testing and counseling into routine care.
  • Develop a framework for implementing coordinated, patient-centered services across specialties, ensuring quality, efficiency, and continuity of care within the genomic clinic model.
3:30 – 5:00 PM
(1.5 hrs)
Syndrome Specific Multidisciplinary Clinics

Speaker: Margaret Harr

  • Describe the structure and function of syndrome-specific multidisciplinary clinics (e.g., for Noonan syndrome, 22q11.2 deletion syndrome, or connective tissue disorders) and how they optimize genomic care delivery.
  • Recognize the roles of clinical and allied health professionals in coordinating care for patients with complex, multisystem genetic syndromes.
  • Evaluate the clinical, psychosocial, and operational benefits of syndrome-specific clinics in improving diagnosis, management, and long-term follow-up outcomes.
5:00 – 5:30 PM
(0.5 hrs)
Closing the Loop: Key Takeaways and Implementation Tools

Speaker: Margaret Harr

  • Summarize the core concepts, quality frameworks, and best practices presented throughout the masterclass, with emphasis on their relevance to clinical genomics and laboratory improvement.
  • Identify practical tools, reference materials, and action plans that participants can use to implement quality assurance measures in their own settings.
  • Commit to specific next steps for applying newly acquired knowledge and skills, including ongoing competency development, EQA participation, and quality improvement initiatives.

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