B-309 Codon 84 as a Potential Molecular Hotspot: Germline VHL p.Val84Met Presenting as Isolated Bilateral Pheochromocytoma

Abstract

Von Hippel–Lindau disease (VHL) is an autosomal dominant cancer predisposition syndrome caused by pathogenic variants in the VHL gene, leading to impaired degradation of hypoxia-inducible factor (HIF) and dysregulated angiogenic signaling. Missense variants are commonly associated with pheochromocytoma-predominant phenotypes; however, codon-level genotype–phenotype correlations remain incompletely defined. Codon 84 lies within the ß-domain of the VHL protein, a region critical for HIF-a binding and assembly of the E3 ubiquitin ligase complex. We report a rare germline p.Val84Met variant presenting as isolated bilateral pheochromocytoma without classic multisystem manifestations, underscoring the diagnostic and interpretive challenges in endocrine laboratory genomics. A 36-year-old woman presented with paroxysmal hypertension, palpitations, diaphoresis, and headache, with a history of poorly controlled hypertension and a sibling who died suddenly at age 21. Plasma free metanephrines were quantified using validated immunoassay methodology, demonstrating normetanephrine levels exceeding two times the upper reference limit. Contrast-enhanced computed tomography identified bilateral adrenal masses (left 47 mm with necrosis; right 16 mm). Comprehensive germline testing was performed using next-generation sequencing targeting established pheochromocytoma–paraganglioma susceptibility genes, including VHL, RET, NF1, SDHB, SDHC, SDHD, and MAX. Variant interpretation followed ACMG/AMP standards incorporating ClinGen VHL Expert Panel specifications. Population databases (gnomAD), in silico predictive algorithms, conservation analysis, and published codon-specific data were systematically reviewed. Radiologic findings were consistent with bilateral pheochromocytomas. Baseline ophthalmologic, neurologic, and abdominal imaging revealed no retinal hemangioblastomas, central nervous system lesions, renal cell carcinoma, or endolymphatic sac tumors. Genetic analysis identified a heterozygous VHL exon 1 missense variant (c.250G>A; p.Val84Met). The variant was absent from large population databases and affects a highly conserved residue within the ß-domain. Pathogenic substitutions at the same codon (e.g., p.Val84Leu) have been previously reported, supporting codon-level functional relevance. Multiple computational tools predicted deleterious impact on protein structure and HIF interaction.According to ACMG/ClinGen VHL Variant Curation Expert Panel specifications, p.Val84Met meets criteria including location in a functionally critical domain (PM1), absence or extreme rarity in population databases (PM2), other pathogenic missense changes at the same codon (PM5), deleterious predictions on multiple algorithms (PP3), and supportive case-level data when observed in unrelated affected individuals with enrichment over controls (PS4), overall supporting classification as a likely pathogenic variant Following appropriate preoperative a-adrenergic blockade, the patient underwent bilateral adrenalectomy with biochemical normalization of catecholamine excess. Lifelong glucocorticoid and mineralocorticoid replacement was initiated, and structured VHL surveillance was implemented. This case refines the pathogenic landscape of codon 84 and supports p.Val84Met as a clinically significant variant associated with pheochromocytoma-predominant VHL. The absence of classical VHL manifestations at presentation highlights the phenotypic variability of missense variants within the ß-domain. Recognition of this variant broadens the genotypic spectrum of VHL and underscores the importance of comprehensive germline testing in bilateral pheochromocytoma, even when syndromic features are subtle. Early molecular diagnosis enables risk adapted surveillance, informs genetic counseling for at risk relatives, and guides surgical and endocrine management in patients with hereditary pheochromocytoma