Five evidence questions to ask before an FH variant review

Why the evidence needs structure

The ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel adapted the ACMG/AMP framework for LDLR. Its specifications address population frequency, loss-of-function variants, functional studies, cosegregation, and computational prediction.

That breadth is the practical problem. One score or database entry cannot carry the full review. Teams need a visible record of what supports a conclusion, what challenges it, and what is still missing.

1. 01

   Is the observed population frequency compatible?

   Check the relevant population, coverage, filtering frequency, and disease context before treating rarity or prevalence as evidence.

   Read the population-frequency guide →
2. 02

   What molecular consequence is proposed?

   Keep the gene, transcript, variant type, and predicted consequence together. A missense change and a predicted loss-of-function variant raise different questions.

3. 03

   What does computational evidence add?

   Use calibrated predictions as supporting evidence. Record the model, threshold, and limitations rather than treating a score as the final classification.

   Read the computational-evidence guide →
4. 04

   Is there functional, segregation, or case evidence?

   Look for validated functional studies, observations in affected individuals, segregation, and phenotype specificity. Record provenance and quality.

5. 05

   Where does the evidence disagree?

   Make conflicts and missing evidence explicit. A review-ready workspace should preserve uncertainty instead of smoothing it away.