ClinVar Genomic variation as it relates to human health

Variant summary: The TTR c.250T>C (p.Phe84Leu) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant is absent in 121202 control chromosomes. The variant has been reported in numerous affected individuals in the literature and has been classified as pathogenic by a reputable database. Taken together, this variant is classified as pathogenic.

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; This variant is associated with the following publications: (PMID: 22592564, 24395461, 31589614, 27350016, 34668655, 26428663, 22745357, 35095067, 34658264, 34207092, 2046936, 30811423, 23279339, 8721565, 28188196, 28635949)

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 84 of the TTR protein (p.Phe84Leu). This variant is present in population databases (rs121918091, gnomAD 0.0009%). This missense change has been observed in individuals with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 2046936, 8721565, 22745357, 23279339, 28635949). This variant is also known as p.Phe64Leu. ClinVar contains an entry for this variant (Variation ID: 13453). 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 with a positive predictive value of 95%. This variant disrupts the p.Phe84 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10488818, 15820680). 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.

The TTR c.250T>C; p.Phe84Leu variant (rs121918091), also known as Phe64Leu, is published in the medical literature in numerous individuals and families with transthyretin-related amyloidosis (Benson 2007, Ii 1991, Rapezzi 2013, Russo 2012). The variant is listed in the ClinVar database (Variation ID: 13453) but is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The phenylalanine at codon 84 is highly conserved and other amino acid substitutions at this codon (c.252T>G; p.Phe84Leu and c.251T>C; p.Phe84Ser) are reported in individuals with transthyretin-related amyloidosis (Benson 2007, Rapezzi 2013, Uemichi 1999). Considering available information, the c.250T>C; p.Phe84Leu variant is classified as pathogenic. References: Benson MD and Kincaid JC. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve. 2007 Oct;36(4):411-23. PMID: 17554795. Ii S et al. Two-tiered DNA-based diagnosis of transthyretin amyloidosis reveals two novel point mutations. Neurology. 1991 Jun;41(6):893-8. PMID: 2046936. Rapezzi C et al. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur Heart J. 2013 Feb;34(7):520-8. PMID: 22745357. Russo M et al. Transthyretin-related familial amyloidotic polyneuropathy: description of a cohort of patients with Leu64 mutation and late onset. J Peripher Nerv Syst. 2012 Dec;17(4):385-90. PMID: 23279339. Uemichi T et al. Oculoleptomeningeal amyloidosis associated with a new transthyretin variant Ser64. Arch Neurol. 1999 Sep;56(9):1152-5. PMID: 10488818.

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with hereditary transthyretin-related amyloidosis. In some published literature, this variant is referred to as p.Phe64Leu. This variant results in the same amino acid change as another variant considered to be pathogenic (c.252T>G). Assessment of experimental evidence suggests this variant results in abnormal protein function. Patient-derived samples containing this variant displayed decreased stability of TTR tetramers (PMID 17503405).

The c.250T>C (p.F84L) alteration is located in exon 3 (coding exon 3) of the TTR gene. This alteration results from a T to C substitution at nucleotide position 250, causing the phenylalanine (F) at amino acid position 84 to be replaced by a leucine (L). Based on data from gnomAD, the C allele has an overall frequency of <0.001% (1/251440) total alleles studied. The highest observed frequency was 0.001% (1/113734) of European (non-Finnish) alleles. This variant was first reported in an individual with peripheral neuropathy, autonomic symptoms, and cardiac and GI involvement with amyloid deposits confirmed on biopsy (Ii, 1991). This variant has been reported in multiple families from Italy and may be associated with disease onset in the sixth to seventh decade (Ferlini, 1996; Russo, 2012; Luigetti, 2013; Cortese, 2017; Iorio, 2017). Type B fibrils, which consist of full-length peptides and can have an impact on the phenotype of the disease, have been found in individuals with this variant (Suhr, 2019). This nucleotide position is highly conserved in available vertebrate species. Functional analysis suggests this variant results in a decrease in the stability of the protein structure (Altland, 2007). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.