ClinVar Genomic variation as it relates to human health

The TTR c.157T>C; p.Phe53Leu variant (rs121918068), also known as Phe33Leu, is reported in the literature in multiple individuals affected with TTR amyloidosis or amyloid polyneuropathy (Altland 2007, Barreiros 2010, Chen 2014, Connors 2003, Ihse 2013, Ii 1991). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The phenylalanine at codon 53 is moderately conserved, and functional studies show altered multimerization properties (Altland 2007). Additionally, other amino acid substitutions at this codon (Cys, Ile, and Val) have been reported in individuals with TTR amyloidosis and are considered disease-causing (Altland 2007, Connors 2003, Venkatesh 2017). Based on available information, the p.Phe53Leu variant is considered to be pathogenic. References: Altland K et al. Genetic microheterogeneity of human transthyretin detected by IEF. Electrophoresis. 2007 Jun;28(12):2053-64. Barreiros AP et al. Liver transplantation and combined liver-heart transplantation in patients with familial amyloid polyneuropathy: a single-center experience. Liver Transpl. 2010 Mar;16(3):314-23. Chen CH et al. A case of familial amyloidotic polyneuropathy with a rare Phe33Leu mutation in the TTR gene. J Formos Med Assoc. 2014 Aug;113(8):575-6. Connors LH et al. Tabulation of human transthyretin (TTR) variants, 2003. Amyloid. 2003 Sep;10(3):160-84. Ihse E et al. Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis. Amyloid. 2013 Sep;20(3):142-50. Ii S et al. Two-tiered DNA-based diagnosis of transthyretin amyloidosis reveals two novel point mutations. Neurology. 1991 Jun;41(6):893-8. Venkatesh P et al. Vitreous Amyloidosis: Ocular, Systemic, and Genetic Insights. Ophthalmology. 2017 Jul;124(7):1014-1022.

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 53 of the TTR protein (p.Phe53Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary transthyretin-mediated (hATTR) amyloidosis (PMID: 1932142, 2046936, 9798666, 17503405, 20209591, 23713495). This variant is also known as Phe33Leu (F33L). ClinVar contains an entry for this variant (Variation ID: 13456). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TTR protein function. This variant disrupts the p.Phe53 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15478468, 17503405, 20558946, 22745357). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

This variant has been identified in multiple individuals with transthyretin-related amyloidosis and/or amyloid cardiomyopathy. In some published literature, this variant is referred to as Phe33Leu. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools predict this variant is damaging.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect; the variant destabilizes TTR monomers (Altland et al., 2007); This variant is associated with the following publications: (PMID: 9798666, 26521788, 31932463, 1932142, 20209591, 2046936, 33373035, 32789836, 34440326, 33739616, 23713495, 17503405)

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.