Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database.

ABSTRACT: Incomplete penetrance, or absence of disease phenotype in an individual with a disease-associated variant, is a major challenge in variant interpretation. Studying individuals with apparent incomplete penetrance can shed light on underlying drivers of altered phenotype penetrance. Here, we investigate clinically relevant variants from ClinVar in 807,162 individuals from the Genome Aggregation Database (gnomAD), demonstrating improved representation in gnomAD version 4. We then conduct a comprehensive case-by-case assessment of 734 predicted loss of function variants in 77 genes associated with severe, early-onset, highly penetrant haploinsufficient disease. Here, we identify explanations for the presumed lack of disease manifestation in 701 of 734 variants (95%). Individuals with unexplain

SUBMITTER: Gudmundsson S 

PROVIDER: S-EPMC12579199 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature