Management of Mitochondrial Trifunctional Protein Variant of Uncertain Significance

Core Management Principle

A variant of uncertain significance (VUS) in mitochondrial trifunctional protein genes should not be used to guide clinical management or dietary interventions, and the patient should be managed based on their clinical phenotype and family history alone, not the genetic finding, as recommended by the American Heart Association and the American College of Medical Genetics and Genomics 1, 2
VUS results represent indeterminate findings with insufficient evidence for pathogenicity and must not direct clinical decisions, according to the American Society of Clinical Oncology and the National Comprehensive Cancer Network 1, 3, 4
Most VUS are eventually reclassified as benign, with 97% of reclassified VUS being downgraded to benign, making premature intervention potentially harmful, as reported by the British Journal of Cancer and the American College of Medical Genetics and Genomics 5

If the patient is symptomatic, proceed with functional testing, including acylcarnitine profile, enzymatic analysis, and fatty acid oxidation flux studies, to establish a biochemical diagnosis, as recommended by the American College of Medical Genetics and Genomics 1, 7

Refer the patient to research studies and variant reclassification programs to help resolve the variant's significance, as recommended by the National Comprehensive Cancer Network and the American College of Medical Genetics and Genomics 6
If affected family members exist with confirmed mitochondrial trifunctional protein deficiency, test them first to determine if the VUS segregates with disease, as recommended by the American Society of Transplantation and the American Heart Association 7, 1

Establish a recontact system with the genetics laboratory every 1-2 years for variant reclassification updates, as recommended by the National Comprehensive Cancer Network and the American College of Medical Genetics and Genomics 6, 2
Document clearly in the medical record that clinical decisions should not be based on the VUS to prevent mismanagement by other providers, as recommended by the American Society of Clinical Oncology and the National Comprehensive Cancer Network 3, 4
Provide genetic counseling emphasizing that VUS should not be used for predictive testing of family members, as recommended by the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors 2

Avoid implementing dietary modifications or restricting exercise in asymptomatic VUS carriers, as this imposes unnecessary burden on asymptomatic individuals, as recommended by the American Heart Association and the American College of Sports Medicine 1, 2
Avoid cascade testing of family members until the variant is reclassified as pathogenic or likely pathogenic, as recommended by the American College of Medical Genetics and Genomics and the National Comprehensive Cancer Network 1, 2
Be aware that direct-to-consumer or broad panel testing increases VUS detection rates, particularly in genes like HADHA/HADHB, as reported by the American Journal of Transplantation and the American College of Medical Genetics and Genomics 7, 2