Objective: To describe the clinical phenotype of a patient with Parkinson’s disease who carries a rare heterozygous variant of GBA c.1157T>G (p.F386C) and to analyze its possible structural and pathogenetic consequences within the framework of the lysosomal model of neurodegeneration.

Background: GBA gene mutation variants are the most significant genetic factor in the development of Parkinson’s disease, Gaucher disease, dementia with Lewy bodies, and RBD. There are well-studied and common alleles and poorly studied and uncommon ones. In their review, Giulietta M. Riboldi et al. systematized the genetic phenotypes of GBA associated with PD. In a multicenter analysis, Sidransky et al. in 2009 proved for the first time the role of GBA as a genetic risk factor for the development of Parkinson’s disease. According to a review of the literature, the c.1157T>G (p.F386C) phenotype is associated with Gaucher disease. However, it is possible that it is an unexplored risk phenotype for the development of Parkinson’s disease.

Method: A search query was performed in Google Scholar, Cochrane Library, and PubMed using the keywords Parkinson’s disease, GBA, c.1157T>G (p.F386C). A comprehensive neurological evaluation and targeted genetic testing of a patient with clinically established PD were performed.

Results: We would like to present the case of a young 40-year-old patient with early-onset Parkinson’s disease with asymmetric onset of symptoms on the left side and rapid progression. The second side was involved 3 years after the onset of the disease.The disease debuted at age 36 with a good response to levodopa. Whole-genome sequencing revealed a heterozygous variant GBA1 exon9:c.T1157G (p.Phe386Cys), classified as VUS. The variant is absent in population databases, but is likely to be functionally significant, allowing it to be considered a possible genetic risk factor for Parkinson’s disease.

Conclusion: The p.F386C substitution expands the spectrum of rare GBA variants associated with Parkinson’s disease. The presented case highlights the need for systematic characterization of rare GBA variants and integration of genetic, structural, and clinical data to refine genotype-phenotype correlations in GBA-associated PD.

Rare missense variants such as p.F386C may represent an underestimated contribution to the risk of developing Parkinson’s disease and require further functional validation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/rare-gba-c-1157tg-p-f386c-variant-in-parkinsons-disease-case-study/