Abstract 4362115: Lack of Genetic Ancestral Diversity is a Major Driver of Clinically Meaningful Changes in Variant Pathogenicity Classification for Reportable Cardiovascular Disease-associated Genes

Introduction/Background: Genetic heart disease encompasses potentially life-threatening conditions, necessitating accurate interpretation of genetic testing. Results range from diagnostic (pathogenic/likely pathogenic (P/LP) or benign/likely benign (B/LB)) to non-diagnostic (conflicting/variant of uncertain significance, C/VUS). Change in these classifications could potentially lead to over- or under-diagnosis and treatment. Research Questions/Hypothesis: We hypothesize that in the American College of Medical Genetics (ACMG) clinically actionable genes, rates of variant pathogenicity evolution towards uncertainty are highest in the cardiovascular (CV) subset, and that underrepresentation of individuals with non-European ancestry in existing genomic cohorts is an uncertainty driver. We aim to determine drivers of variant pathogenicity evolution in these genes. Methods/Approach: ClinVar variants evaluated from 01/2011-12/2024 were used. The ACMG SF v3.3 list serves as our 84 genes of interest (ACMG 84), with 41 in the CV subset. GnomAD v4.1.0 is our genomic database. We defined an uncertainty coefficient (UC) to evaluate diagnostic certainty of variants over time. Date of equipoise quantifies when uncertainty of a variant class transitions from uncertain to neutral certainty. We defined a downgraded discordant group of variants that changed from P/LP to C/VUS or B/LB and were above minor allele frequency (MAF) of 1E^-4 in one ancestry group (European or non-European) and below that threshold in the other ancestry group. Results/Data: Number of evaluated variants and VUSs have generally been increasing between 2011-2024, peaking at 144,098 variants in 2024 and 63,041 VUSs in 2021. In the ACMG 84 group and CV subset, 12.95% and 11.43% of variants underwent a change between P/LP, C, VUS, or B/LB from 2011-2024, respectively. Of ACMG 84 subgroup UCs, the CV group had the latest date of equipoise. The percentage of downgraded discordant variants common in non- European ancestry group was 9.2-fold higher than the downgraded discordant variants considered common in the European ancestry group in ACMG 84 genes, and 7.2-fold higher in the CV subset. Conclusions: Uncertainty in pathogenicity assignment over time is marked in the ACMG 84 CV subset, also highlighting the slow progress in clarifying it. Findings support that underrepresentation of individuals of non-European ancestry in current investigation is a potential diagnostic uncertainty driver.