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Abstract: SA-PO558

Potentially Clinically Relevant Variant of Uncertain Significance in the COL4A5 Gene

Session Information

  • Genetic Diseases: Diagnosis
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic


  • Trinka, Teresa, The Warren Alpert Medical School at Brown University, Providence, Rhode Island, United States
  • Gaj, Kerry, Natera, Inc., Austin, Texas, United States
  • Stein, Quinn P., Natera, Inc., Austin, Texas, United States
  • Punj, Sumit, Natera, Inc., Austin, Texas, United States
  • Faizan, Mohammed Khurram, Hasbro Children's Hospital, Providence, Rhode Island, United States

Genetic testing is an emerging tool for patient management in the field of Nephrology. Numerous studies highlight the benefits of using broad, unbiased genetic panels compared to smaller, targeted panels based on the clinical presentation of the disease, due to the often complex and variable presentation of many renal disorders. Alport syndrome (AS) is an inherited disease caused by pathogenic variants in the COL4A3/A4/A5 genes that encode collagen IV components respectively. In AS, a spectrum of phenotypes ranging from isolated hematuria with non-progressive renal disease to progressive renal disease with extrarenal abnormalities is observed. Here we report our findings of a variant of uncertain significance (VUS) in the COL4A5 gene in four family members.

Case Description

Patient 0 was a 16 y/o female, initially presenting with microscopic hematuria and marginally elevated urine protein to creatinine ratio. The patient’s physical exam was unremarkable with normal blood pressure and SCr levels. However, the patient’s mother and maternal aunt both had a lifelong history of microscopic hematuria. The maternal grandfather had lifelong kidney disease, for which he received a kidney transplant at the age of 50. All four patients underwent genetic testing with a next generation sequencing (NGS)-based panel consisting of 385 genes associated with kidney disease (the RenasightTM test). No positive genetic findings were identified in the patients; however, a VUS, c.276+2dup, in the COL4A5 gene was identified in all four members.


In the family presented here, genetic testing provided an intimation of a possible cause and inheritance pattern for kidney disease and hematuria. Genetic testing for Patient 0 gave rise to cascade testing in 3 additional family members to date, with the potential for testing of other affected family members. The VUS identified is predicted to affect the highly conserved splice donor site for exon 4. Functional studies are necessary to determine the impact of this variant and to invoke stronger evidence for reclassification. To our knowledge, this variant has not been reported to be associated with AS and is absent from population databases. However, based on the clinical presentation of these patients and the lack of other positive genetic findings, this VUS is suspicious and warrants further investigations.