Three hereditary transthyretin amyloidosis (hATTR) genetic variants previously classified as variants of uncertain significance (VUS) have been reclassified as variants likely pathogenic (VLP), giving them potential diagnostic utility, according to a recently published article in Neurology and Therapy.
hATTR occurs due to single base pair substitutions in the transthyretin (TTR) gene, known as missense pathogenic variants, that lead to the production of abnormal TTR protein, which in turn causes the aggregation of insoluble amyloid deposits. To date, more than 130 missense pathogenic variants have been identified, with many of them being VUS. This, therefore, has created a subset of patients in which the diagnosis is uncertain.
“Most VUS likely reflect benign genetic variations present in the human genome,” the authors wrote, “however, a small percentage of VUS have the potential to cause disease and ultimately can be reclassified to a variant likely pathogenic (VLP).”
Because of the importance of an early diagnosis in slowing disease progression and improving survival, there is a growing interest in assessing data produced by genetic testing programs to reclassify VUSs where possible.
Read more about hATTR etiology
The authors used data from the COMPASS program, which offers genetic testing to patients with a family history of hATTR or symptoms suggestive of the disease in the United States and Canada, to reclassify VUSs into VLPs. Reclassification was made according to the recommendations of the American College of Medical Genetics and Genomics (ACMG).
As a result, c.172G>C (p.D58H), c.194C>T (p.A65V), and c.239C>T (p.T80I) have been reclassified into VLPs. To date, no VUSs have been reclassified into benign variants as a result of this study.
The authors emphasize the growing importance of implementing genetic information into clinical practice, recommending the discussion of the possibility of variant reclassification as well as establishing a plan of follow-up and direct communication between physicians and patients with a VUS.
“With the availability of novel therapies that alter the natural disease course of [hATTR], reclassification of these variants will increase the likelihood that patients will receive early and appropriate treatment,” the authors concluded.
Patel JK, Rosen AM, Chamberlin A, et al. Three newly recognized likely pathogenic gene variants associated with hereditary transthyretin amyloidosis. Neurol Ther. Published online August 6, 2022. doi.org/10.1007/s40120-022-00385-1