ClinVar Genomic variation as it relates to human health

This variant has not been reported in the literature in individuals affected with TTR-related conditions. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Lys55 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16076613, 19467548, 21843040; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 55 of the TTR protein (p.Lys55Glu).

The p.K55E variant (also known as c.163A>G), located in coding exon 2 of the TTR gene, results from an A to G substitution at nucleotide position 163. The lysine at codon 55 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in an individual with concerns for transthyretin (TTR) amyloidosis (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.