ClinVar Genomic variation as it relates to human health

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala140Ser (also reported as p.Ala120Ser) variant in TTR has been reported in 2 individual s with clinical features of familial transthyretin amyloidosis (Lachmann 2002, C onnors 2003, Luigetti 2013) and was absent from large population studies. Comput ational prediction tools and conservation analysis suggest that the p.Ala140Ser variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pat hogenic role, the clinical significance of the clinical significance of the p.Al a140Ser variant is uncertain.

Variant summary: The TTR c.418G>T (p.Ala140Ser) variant located in the beta strand 11 (via Polimanti_2014) involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. This variant is absent in 121370 control chromosomes (ExAC). Multiple publications have cited the variant, however, due to geographical/site overlap, it seems as though the same two affected patients are being cited, therefore, there is limited available clinical studies. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Until functional data and additional clinical data become available, this variant is classified as a "Variant of Uncertain Significance - Possibly Pathogenic."

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 140 of the TTR protein (p.Ala140Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial transthyretin amyloidosis (PMID: 12050338, 22592564, 26208957, 28635949). This variant is also known as p.Ala120Ser. ClinVar contains an entry for this variant (Variation ID: 229597). 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.Ala140 amino acid residue in TTR. Other variant(s) that disrupt this residue have been observed in individuals with TTR-related conditions (PMID: 12050338, 22209138, 26208957, 28635949), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

The p.A140S variant (also known as c.418G>T and p.A120S), located in coding exon 4 of the TTR gene, results from a G to T substitution at nucleotide position 418. The alanine at codon 140 is replaced by serine, an amino acid with similar properties. This variant (also referred to as p.A120S) has been reported in individuals with features consistent with transthyretin (TTR) amyloidosis (Gürsoy AE et al. Neurol India;66:238-241; Patel K et al. Amyloid, 2018 09;25:211-212; Iorio A et al. Eur J Hum Genet, 2017 09;25:1055-1060; Shibata Y et al. Amyloid, 2017 03;24:66-67; Luigetti M et al. Neurol Sci, 2013 Jul;34:1057-63; Lachmann HJ et al. N Engl J Med, 2002 Jun;346:1786-91; Adams D et al. Neurology, 2015 Aug;85:675-82; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.