ClinVar

Description

The p.F53L pathogenic mutation (also known as c.157T>C), located in coding exon 2 of the TTR gene, results from a T to C substitution at nucleotide position 157. The phenylalanine at codon 53 is replaced by leucine, an amino acid with highly similar properties. This alteration, which is also known as p.F33L, was first reported in a Polish-American individual who developed symptoms of autonomic dysfunction and neuropathy at 53 years of age; a sural nerve biopsy showed the presence of amyloid and immunohistochemistry revealed transthyretin (Ii S et al. Neurology, 1991 Jun;41:893-8). This variant has been identified in individuals of Polish, Swedish, Ashkenazi Jewish, and Asian ancestry with symptoms of familial amyloidotic polyneuropathy (Harding J et al. Biochim Biophys Acta. 1991; 1097(3):183-6; Holmgren G et al. Amyloid. 2005; 12(3):189-92; Leibou L et al. Isr Med Assoc J. 2012; 14(11):662-5; Chen CH et al. J Formos Med Assoc. 2014; 113(8):575-6). A functional study of urea gradients found this alteration resulted in decreased conformational stability of the monomer molecule (Altland K et al. Electrophoresis. 2007; 28(12):2053-64). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.