Course objective: Develop hands-on proficiency in interpreting next-generation sequencing data, annotating variants using professional clinical tools, and classifying variants using the full ACMG/AMP evidence framework — the core daily competency of a variant scientist in a California clinical genetics laboratory.

• NGS data fundamentals — FASTQ, BAM, VCF file formats, quality metrics, read depth, coverage uniformity, understanding what the lab produces before variant analysis begins
• IGV — Integrative Genomics Viewer — loading BAM and VCF files, inspecting variant calls, identifying artefacts, strand bias, alignment issues, and low-quality calls
• Variant annotation workflow — VEP and ANNOVAR pipelines, consequence terms, canonical transcript selection, picking the right RefSeq transcript for clinical reporting
• gnomAD v4 — allele frequency lookup, popmax filtering, population stratification, constraint metrics pLI and LOEUF, distinguishing benign common variants from rare candidates
• ClinVar — record structure, star review status, submitter categories, conflicting interpretations, understanding why the same variant has different classifications across submitters
• OMIM and HGMD — gene-disease relationship navigation, phenotypic series, mutation types, accessing allelic variants, using OMIM for clinical correlation
• ACMG/AMP framework overview — the 28 evidence codes, pathogenic versus benign spectrum, combining evidence, the five-tier classification system, how a variant moves from VUS to pathogenic
• Pathogenic evidence codes I — PVS1 (null variant), PS1 (same amino acid change), PS2 (de novo confirmed), PS3 (functional studies), PS4 (prevalence in affected), applying each with real variants
• Pathogenic evidence codes II — PM1 through PM6 and PP1 through PP5, mutational hotspot criteria, computational evidence thresholds, co-segregation evidence requirements
• Benign evidence codes — BA1, BS1 through BS4, BP1 through BP7, allele frequency thresholds, lack of segregation, synonymous variants, applying ACMG benign criteria systematically
• VUS management — what a VUS means clinically, the four VUS sub-categories, common reasons for VUS, how VUS are tracked and reclassified over time, communicating VUS to ordering physicians
• Germline variant classification workshop I — classify 8 real variants from hereditary cancer cases (BRCA1, BRCA2, MLH1, MSH2) using gnomAD, ClinVar, OMIM, and all applicable ACMG codes
• Germline variant classification workshop II — classify 8 real variants from rare disease cases (PKU, SMA, CF, Rett syndrome) applying ACMG framework with gene-specific considerations
• Somatic variant classification — AMP/ASCO/CAP 2017 tiering system (Tier I through IV), distinction from germline ACMG classification, oncogenicity classification, clinical actionability
• CIViC, OncoKB, and COSMIC — somatic variant databases, evidence levels, clinical trial matching, FDA approved therapies tied to specific somatic variants, using databases for actionability
• Splice variant interpretation — SpliceAI scores, MaxEntScan, RT-PCR evidence requirements, ACMG PVS1 splicing criteria, classifying canonical and non-canonical splice variants
• Copy number variant interpretation — ACMG CNV classification framework, log2 ratio interpretation, BAF patterns, gene content assessment, DECIPHER and ClinGen dosage sensitivity
• Variant classification case study I — full worked case, hereditary breast and ovarian cancer WES trio, variant identification through classification, written interpretation statement
• Variant classification case study II — full worked case, paediatric rare disease WES, de novo variant identification, ACMG classification, clinical significance statement
• ACMG secondary findings — SF3.2 gene list, criteria for reporting incidental findings, patient preferences, reporting obligations, navigating secondary findings in clinical reports

Course objective: Develop the clinical knowledge and documentation skills required to function effectively in a California clinical genetics environment — understanding how genetic information is generated, interpreted, communicated, and regulated across hereditary disease, oncology, and reproductive genetics practice.

• Genetics consultation workflow — referral indications, pre-test counselling components, informed consent for genetic testing, test selection criteria, turnaround time expectations
• Pedigree construction — standard PGNC symbols, three-generation minimum, proband notation, documenting family history accurately, common pedigree errors and how to avoid them
• Inheritance pattern recognition from pedigrees — autosomal dominant, autosomal recessive, X-linked, mitochondrial — identifying patterns from family history data and selecting appropriate tests
• Hereditary cancer genetics I — BRCA1/2 testing criteria, Lynch syndrome MSH2/MLH1/MSH6/PMS2, NCCN guidelines for hereditary breast and ovarian cancer, variant interpretation in cancer predisposition genes
• Hereditary cancer genetics II — hereditary risk assessment, risk models (BRCAPro, Tyrer-Cuzick, MMRpro), cascade testing in families, risk-reducing intervention options, BRCA1 family case study
• Rare disease diagnosis workflow — phenotype-first approach, HPO term assignment, OMIM phenotypic series navigation, GeneMatcher, differential diagnosis construction, test sequencing strategy
• Paediatric genetics and developmental delay — intellectual disability workup, chromosomal microarray first-line, WES trio indication criteria, ACMG guidelines for DD/ID evaluation
• Metabolic genetics and newborn screening — California NBS 80+ condition panel, positive NBS follow-up workflow, enzyme assays, amino acid profiles, organic acids, PKU case study
• Clinical genetics report writing I — anatomy of a clinical genetics report, ACMG/CAP required elements, variant description using HGVS nomenclature, clinical significance statement structure
• Clinical genetics report writing II — writing the interpretation section, clinical correlation statement, recommendation language, follow-up testing suggestions, amendment and addendum procedures
• Clinical genetics report writing workshop — write three complete clinical genetics reports from de-identified case data — hereditary cancer panel, WES rare disease, chromosomal microarray — with faculty graded feedback
• Cardiovascular genetics — hypertrophic cardiomyopathy (MYBPC3, MYH7), Long QT syndrome (KCNQ1, KCNH2, SCN5A), arrhythmogenic cardiomyopathy, cascade testing, variant interpretation in cardiac genes
• Neurogenetics — Duchenne/Becker muscular dystrophy, spinal muscular atrophy, Huntington disease, fragile X syndrome, testing algorithms, repeat expansion analysis, MLPAi nterpretation
• Prenatal genetics — NIPT clinical utility and limitations, chromosomal microarray in prenatal diagnosis, CVS versus amniocentesis indications, positive NIPT follow-up, VUS in prenatal context
• Reproductive genetics — carrier screening expansion panels, residual risk calculation, autosomal recessive carrier coupling, ACMG/ACOG carrier screening guidelines, preimplantation genetic testing
• CDPH, CLIA, and CAP regulatory framework — California clinical laboratory licensing, CLIA certificate types, CAP accreditation checklist requirements, proficiency testing, quality assurance documentation
• LIMS and laboratory information management — test ordering workflows, result release procedures, critical value reporting, amendment procedures, chain of custody documentation
• HIPAA and genetic information privacy — GINA protections and limitations, California Genetic Information Nondiscrimination Act, de-identification standards, patient authorization for data sharing
• Multidisciplinary team roles in clinical genetics — ABMGG-certified clinical geneticist, ABGC-certified genetic counsellor, CLS (Genetics), CGMBS, laboratory director qualifications, scope of practice boundaries
• Mock clinical genetics case conference — present one complete case to the cohort including family history, test selection rationale, variant classification, report interpretation, and clinical recommendations

Course objective: Build applied knowledge in pharmacogenomics and precision oncology — two of the fastest-growing sectors in California's clinical genomics workforce — and complete a structured career preparation program including portfolio development, interview preparation, and ASCP BOC examination strategy.

• Pharmacogenomics foundations — drug metabolism pathways, pharmacokinetic versus pharmacodynamic PGx, the star allele nomenclature system, haplotype-to-diplotype-to-phenotype translation
• CYP2D6 — the most clinically important PGx gene, star allele calling, metaboliser phenotypes (PM/IM/NM/UM), CPIC guidelines for codeine, tramadol, antidepressants, antipsychotics
• CYP2C19 — clopidogrel and the Black Box Warning, proton pump inhibitors, antidepressants, CPIC recommendation tiers, clinical decision support alert implementation
• CYP2C9 and VKORC1 — warfarin pharmacogenomics, bleeding risk prediction, dose algorithms, FDA label updates, clinical utility in anticoagulation management
• DPYD and fluoropyrimidines — 5-fluorouracil and capecitabine severe toxicity risk, DPYD*2A and c.2846A>T variants, CPIC dose reduction guidelines, pre-treatment testing recommendations
• TPMT and NUDT15 — thiopurine toxicity in ALL and IBD, TPMT star alleles, NUDT15 Asian population frequency, dose adjustment guidance, paediatric oncology PGx application
• PharmGKB and CPIC resources — database navigation, clinical annotation levels, CPIC guideline structure, DPWG guidelines, prescribing recommendations integration into clinical reports
• PGx clinical report structure — genotype result, predicted phenotype, drug-gene interaction summary, clinical recommendation, evidence grade, CPIC tier, report writing workshop
• Precision oncology foundations — somatic mutation landscape, driver versus passenger mutations, oncogene addiction, tumour suppressor loss, synthetic lethality, DNA damage repair pathways
• Actionable oncology biomarkers — TMB (tumour mutational burden), MSI (microsatellite instability), HRD (homologous recombination deficiency), PD-L1 expression, FDA companion diagnostic approvals
• Liquid biopsy and circulating tumour DNA — cfDNA biology, ctDNA detection methods, clinical applications in treatment monitoring, resistance mutation detection, minimal residual disease
• Precision oncology case studies — NSCLC EGFR/ALK/ROS1 testing and targeted therapy selection, breast cancer HER2/ESR1, colorectal cancer RAS/BRAF, melanoma BRAF V600E, using OncoKB for actionability
• Gene therapy landscape — approved products in California clinical practice (Zolgensma for SMA, Hemgenix for haemophilia B, Casgevy for sickle cell), patient eligibility criteria, pre-treatment genetic testing requirements
• ASCP BOC Molecular Biology examination — exam structure, content domains, question types, CLS versus MB pathway comparison, recommended study resources, practice question strategy
• California CGMBS licence — CDPH licensing requirements, qualifying laboratory experience documentation, examination registration, continuing education requirements, licence maintenance
• California genomics job market — current demand by employer type, salary ranges for variant analyst versus lab coordinator versus PGx specialist, geographic distribution of roles, Inland Empire versus Bay Area versus LA
• Resume and CV for clinical genomics roles — structuring a genomics CV, describing coursework as relevant experience, highlighting ACMG case study work, what hiring managers look for, LinkedIn profile optimisation
• Portfolio development — compiling the three clinical genetics reports from L02 as portfolio pieces, capstone variant classification case as a portfolio demonstration, GitHub for genomics coursework if applicable
• Mock clinical genomics interview — common interview questions at Ambry Genetics, Natera, Kaiser Permanente, BillionToOne, Quest Molecular, answering competency questions without bench experience, demonstrating knowledge depth
• Graduation and cohort presentation — each student presents one variant classification case to the cohort and faculty, demonstrating mastery of ACMG framework, clinical correlation, and report writing, program completion celebration