Submissions for variant NM_000371.4(TTR):c.418G>A (p.Ala140Thr)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV005203487	SCV005838607	uncertain significance	Amyloidosis, hereditary systemic 1	2024-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 140 of the TTR protein (p.Ala140Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of familial transthyretin amyloidosis (PMID: 22209138). This variant is also known as p.Ala120Thr. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TTR protein function with a positive predictive value of 80%. This variant disrupts the p.Ala140 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12050338, 22592564, 26208957, 28635949). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.