Three Newly Recognized Likely Pathogenic Gene Variants Associated with Hereditary Transthyretin Amyloidosis

Abstract

Introduction: Hereditary transthyretin amyloidosis (ATTRv [variant]) is a clinically heterogeneous, progressively debilitating, fatal disease resulting from the deposition of insoluble amyloid fibrils in various organs and tissues. Early diagnosis of ATTRv can be facilitated with genetic testing; however, such testing of the TTR gene identifies variants of uncertain significance (VUS) in a minority of cases, a small percentage of which have the potential to be pathogenic. The Akcea/Ambry VUS Initiative is dedicated to gathering molecular, clinical, and inheritance data for each TTR VUS identified by genetic testing programs to reclassify TTR variants to a clinically actionable status (e.g., variant likely pathogenic [VLP]) where appropriate.

Methods: Classification criteria used here, based on recommendations from the American College of Medical Genetics and Genomics, are stringent and comprehensive, requiring distinct lines of evidence supporting pathogenesis.

Results: Three TTR variants have been reclassified from VUS to VLP, including c.194C>T (p.A65V), c.172G>C (p.D58H), and c.239C>T (p.T80I). In each case, the totality of genetic, structural, and clinical evidence provided strong support for pathogenicity.

Conclusions: Based on several lines of evidence, three TTR VUS were reclassified as VLP, resulting in a high likelihood of disease diagnosis for those and subsequent patients as well as at-risk family members.

Keywords: Hereditary transthyretin amyloidosis; Likely pathogenic variant; Reclassification, variant of uncertain significance; Variant of unknown significance.

Fig. 1

Crystal structure of the TTR protein dimer highlighting the loci of the three variants. The light blue and green colors indicate the individual monomers of the TTR dimer. The green TTR monomer is labeled with select variants. The red text indicates the position of the TTR variants reclassified from VUS to VLP (D58H, A65V, and T80I) and nearby pathogenic variants are shown in black. TTR, transthyretin; VLP variant likely pathogenic, VUS variant of uncertain significance