Abstract: SA-PO0616
Variants of Uncertain Significance Burden Quantification and Reclassification in a Pediatric Kidney Genetics Clinic
Session Information
- Monogenic Kidney Diseases: Tubular and Other
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Salcedo-Giraldo, Jordy, Children's National Hospital, Washington, District of Columbia, United States
- Wink, Krista Renee, Children's National Hospital, Washington, District of Columbia, United States
- Dadzie, Nicholas, Children's National Research & Innovation Campus, Washington, District of Columbia, United States
- Freiman, Andrew, Children's National Hospital, Washington, District of Columbia, United States
- Gulati, Ashima, Children's National Hospital, Washington, District of Columbia, United States
Background
Variants of uncertain significance (VUS) present major challenges in interpreting clinical genetic testing results. Since the ACMG's formal definition of VUS in 2015, VUS reporting has increased. We aimed to quantify VUS burden and re-classify VUS based on variant characteristics and clinical correlation.
Methods
Genetic test results on patients (ages <1-21 years) evaluated in a pediatric kidney genetics clinic with reported VUS but without a pathogenic (P) or likely pathogenic (LP) variant were examined. Genetic test results were stratified into two time periods: 2015–2020 and 2021–2025. Within each period, VUS were re-classified as either VUS-of-interest, defined as those that affected management and clinical outcome measures, or VUS-other.
Results
A total of N=47 patients were identified with VUS-only results from clinical genetic testing. When stratified by time-period, N=9 and N=38 patients were tested between 2015–2020 and 2021–2025, respectively. Of all the VUS detected, N=23 VUS were re-classified as VUS-of-interest (N=9 and N=14 between 2015-2020 and 2021-2025, respectively), while N=205 were VUS-other (all during 2021-2025). Table 1 summarizes the clinical characteristics of patients with VUS-only results and the type of genetic testing obtained, stratified by time and VUS re-classification.
Conclusion
Our findings suggest a shift in the VUS burden with recent years showing an increased reporting of VUS not associated with clinical utility. This may reflect evolving reporting practices and increased use of broader gene panels. These trends highlight the need for structured workflows for responsible VUS interpretation to ensure meaningful integration of genetic data into clinical decision-making.
Characteristics of patients with VUS-only clinical genetic test results stratified by time
| 2015-2020 | 2021-2025 | |||
| VUS-of-interest | VUS-other | VUS-of-interest | VUS-other | |
| Kidney Disease Category | ||||
| Structural | 7 | 0 | 5 | 6 |
| Tubular | 2 | 0 | 4 | 3 |
| Glomerular | 0 | 0 | 1 | 5 |
| Other | 0 | 0 | 4 | 10 |
| Type of test* | ||||
| Limited gene panels | 7 | 0 | 6 | 6 |
| Broad gene panels | 4 | 0 | 9 | 22 |
| Exome or Genome testing | 7 | 0 | 3 | 2 |
*N= number of genetic tests ordered by type, note some patients received multiple types of testing