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

Sanna Gudmundsson (), Moriel Singer-Berk, Sarah L. Stenton, Julia K. Goodrich, Michael W. Wilson, Jonah Einson, Nicholas A. Watts, Tuuli Lappalainen, Heidi L. Rehm, Daniel G. MacArthur and Anne O’Donnell-Luria ()
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Sanna Gudmundsson: Broad Institute of MIT and Harvard
Moriel Singer-Berk: Broad Institute of MIT and Harvard
Sarah L. Stenton: Broad Institute of MIT and Harvard
Julia K. Goodrich: Broad Institute of MIT and Harvard
Michael W. Wilson: Broad Institute of MIT and Harvard
Jonah Einson: New York Genome Center
Nicholas A. Watts: Broad Institute of MIT and Harvard
Tuuli Lappalainen: KTH Royal Institute of Technology
Heidi L. Rehm: Broad Institute of MIT and Harvard
Daniel G. MacArthur: Broad Institute of MIT and Harvard
Anne O’Donnell-Luria: Broad Institute of MIT and Harvard

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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 unexplained lack of disease manifestation in this set of disorders are rare, underscoring the need and power of deep case-by-case assessment presented here to minimize false assignments of disease risk, particularly in unaffected individuals with higher rates of secondary properties that result in rescue.

Date: 2025
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DOI: 10.1038/s41467-025-61698-x

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