Isolated Proteinuria and a Novel CUBN Variant: A Case Report and Diagnostic Considerations

Introduction: Persistent proteinuria with preserved renal function is a common clinical finding that can pose a diagnostic challenge, particularly when laboratory investigations and renal biopsy fail to identify a specific etiology. Variants in the CUBN gene, which encodes cubilin—a key protein in the proximal tubular reabsorption of low-molecular-weight proteins—have increasingly been recognized as a genetic cause of isolated, typically benign proteinuria. Case Description: We report the case of a 31-year-old asymptomatic male who was referred for evaluation of persistent proteinuria detected during routine laboratory testing. He presented with non-nephrotic range proteinuria (~1 g/24h), preserved renal function (serum creatinine 0.9 mg/dL, eGFR >90 mL/min/1.73m2), no hematuria, and no family history of kidney disease. At the age of 24, he underwent a kidney biopsy, which revealed normal glomeruli on light microscopy, apparent thickening of the glomerular basement membrane, and mild foot process effacement on electron microscopy. Immunofluorescence was negative for immune complex deposits. Due to the lack of a defined etiology, a genetic panel for hereditary kidney diseases was performed, revealing a homozygous CUBN variant (chr10:16,915,820 C>A). This variant has not been previously reported in the literature and is considered likely pathogenic, consistent with a diagnosis of isolated proximal tubular proteinuria, without current evidence of progression to chronic kidney disease. Discussion: CUBN gene variants have been associated with both Imerslund-Gräsbeck syndrome and isolated benign proteinuria. The protein cubilin plays an essential role in the reabsorption of filtered proteins in the proximal tubule. When defective, it leads to persistent, typically non-progressive proteinuria. This case exemplifies how genetic testing can elucidate the etiology of proteinuria when conventional diagnostics are inconclusive. Identification of such variants helps avoid unnecessary immunosuppressive therapy, repeated kidney biopsies, and enables targeted long-term monitoring. Moreover, this report underscores the increasing value of genetic analysis in the workup of renal abnormalities. In selected patients, especially those with isolated findings, genetic testing may precede renal biopsy as a non-invasive diagnostic tool.