Inherited Mendelian Disorders and Germline Variant Interpretation
Concepts
Master inheritance patterns (autosomal dominant/recessive, X-linked, mitochondrial, imprinting), penetrance, expressivity, anticipation, and mosaicism. Understand variant nomenclature (HGVS), classification using ACMG/AMP criteria (PVS1, PS1-4, PM1-6, PP1-5, BA1, BS1-4, BP1-7), and the five-tier system (pathogenic, likely pathogenic, VUS, likely benign, benign). Know the evidence types: population frequency (gnomAD), computational predictors, segregation, functional data, de novo status, and allelic data.
Interpretation practice
Be able to apply PVS1 (null variant in a gene where loss of function is a mechanism), PS3 (functional studies), PM2 (absent from controls), and PP3 (computational support). Understand the difference between a VUS and a variant of uncertain significance that should not drive clinical management, and the role of phenotype-specificity (PP4). Know when to pursue RNA studies, functional assays, or family segregation to reclassify.
Traps
Items over-weight computational predictors as standalone evidence, misapply PVS1 to genes where haploinsufficiency is not established, or treat a VUS as actionable. Watch for questions about reduced penetrance, variable expressivity, and the difference between a pathogenic variant and a risk allele (e.g., low-penetrance susceptibility alleles).
Rule of thumb
Classify by combining independent evidence lines; a single strong criterion rarely suffices. A VUS should be reported as uncertain, with a plan for reanalysis, not as a diagnosis. For recessive disease, confirm phase (in trans) before assigning causality.
Worked example
A nonsense variant in a gene where LoF is the known mechanism, absent from gnomAD, with a de novo observation and matching phenotype: PVS1 + PM2 + PS2 + PP4 supports pathogenic. If the same variant were seen in a gene with a gain-of-function mechanism, PVS1 would not apply and the classification would drop.