Abstract Body (Do not enter title and authors here): Introduction:
Cardiomyopathies, including hypertrophic (HCM) and dilated (DCM), are heterogeneous heart muscle disorders contributing significantly to heart failure, arrhythmias, and sudden cardiac death. While guidelines recommend genetic testing for affected individuals and relatives, uncertainty persists due to evolving gene-disease associations and variant interpretations. This study assesses the prevalence and penetrance of ClinVar-annotated variants in cardiomyopathy genes using the AllofUs (AoU) dataset to evaluate updated ClinGen classifications.

Hypothesis:
LP/P variants in genes classified by ClinGen as definitive, strong, or moderate have higher penetrance than those in limited or disputed genes in a population-level cohort.

Methods:
We performed a retrospective cohort study using AoU (n=413,483 with exome data). Variants were filtered for quality (read depth ≥10, genotype quality ≥20); poor-quality samples were excluded. We retained variants in ClinGen-curated DCM and HCM genes, annotated in ClinVar as pathogenic/likely pathogenic (P/LP), variants of uncertain significance (VUS), or benign/likely benign (B/LB) with ≥1-star review status. Phenotypes were defined using ICD-9/10 codes; subclinical disease was defined by codes for heart failure, transplant, arrhythmias, or sudden cardiac death.

Results:
DCM penetrance was low overall but observed only in ClinGen-associated genes of moderate association or stronger. No clinical DCM cases were found in P/LP carriers of genes with limited or disputed ClinGen classification. P/LP variants in definitive/strong/moderate genes showed 4.3% penetrance for DCM versus 0% in Limited/Disputed genes (p<0.001). For subclinical DCM, P/LP variants in definitive/strong/moderate genes showed 15.5% penetrance versus 8.4% in limited/disputed genes (p<0.001).

For HCM, P/LP variants in definitive/strong/moderate genes showed 8.54% penetrance versus 0.9% in limited/disputed genes (p<0.001). For subclinical HCM, penetrance rates were 13.6% vs. 11.31% (p=0.38).

Conclusion:
In a large, population-based cohort, pathogenic variants in DCM and HCM genes with definitive, strong, or moderate ClinGen evidence showed significantly higher clinical and subclinical penetrance than variants in genes with limited or disputed evidence. These findings support recent ClinGen reclassifications and emphasize the importance of gene validity in guiding variant interpretation and clinical decision-making.