Biochemical characterization of the FH variant p.Lys414Glu reveals loss of enzymatic function and disrupted...

Area of Science:

• Genetics
• Oncology
• Biochemistry

Background:

• Germline mutations in fumarate hydratase (FH) are linked to hereditary leiomyomatosis and renal cell carcinoma (HLRCC).
• Variants of Uncertain Significance (VUS) in FH present diagnostic challenges for HLRCC.
• The FH p.Lys414Glu variant has been observed in patients with HLRCC features, necessitating further functional evidence.

Purpose of the Study:

• To functionally characterize the FH p.Lys414Glu variant.
• To determine the pathogenicity of the FH p.Lys414Glu variant.
• To provide evidence for clinical classification and patient management.

Main Methods:

• In vitro functional assays were employed to assess the enzymatic activity of the FH p.Lys414Glu variant.
• Biochemical analyses were conducted to evaluate the impact of the variant on FH protein function.

Main Results:

• The FH p.Lys414Glu variant was found to be completely inactive.
• Loss of fumarate hydratase enzymatic activity was confirmed for the p.Lys414Glu variant.

Conclusions:

• The FH p.Lys414Glu variant should be classified as pathogenic.
• This finding provides critical evidence for the clinical diagnosis and surveillance of HLRCC patients with germline FH p.Lys414Glu.
• Accurate variant classification improves patient management and genetic counseling.