ClinVar

Description

The p.L32V pathogenic mutation (also known as c.94C>G), located in coding exon 2 of the TTR gene, results from a C to G substitution at nucleotide position 94. The leucine at codon 32 is replaced by valine, an amino acid with highly similar properties. This variant (also referred to as p.L12V) has been detected in unrelated index cases with transthyretin amyloidosis with features including polyneuropathy and cardiomyopathy, and was reported to segregate with disease in a family (Martínez-Ulloa PL et al. J Peripher Nerv Syst, 2017 09;22:208-212; Hinderhofer K et al. Amyloid, 2019 Jun;26:85-93). Other variants affecting this codon (e.g., p.L32P and p.L32M) have also been reported in association with amyloidosis (Brett M et al. Brain. 1999 Feb;122 ( Pt 2):183-90; Choi K et al. J Clin Neurol. 2018 Oct;14(4):537-541). Based on internal structural analysis, the p.L32V variant is anticipated to result in a decrease in structural stability (Schormann N et al. Amyloid. 1998 Sep;5(3):175-87). 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 in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.