Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001049648 | SCV001213713 | likely pathogenic | Amyloidosis, hereditary systemic 1 | 2022-11-29 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals affected with TTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 846359). 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 disrupts the p.Glu109 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301926, 10842705, 20209591, 25644864, 28635949, 28911993). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 109 of the TTR protein (p.Glu109Val). |
| Athena Diagnostics | RCV001288935 | SCV001476393 | uncertain significance | not provided | 2020-03-19 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002445262 | SCV002611908 | likely pathogenic | Cardiovascular phenotype | 2024-11-13 | criteria provided, single submitter | clinical testing | The p.E109V variant (also known as c.326A>T), located in coding exon 3 of the TTR gene, results from an A to T substitution at nucleotide position 326. The glutamic acid at codon 109 is replaced by valine, an amino acid with dissimilar properties. This variant (also referred to as Glu89Val) has been detected in individuals with features consistent with TTR amyloidosis (Tomoaia R et al. Med Pharm Rep, 2021 Aug;94:S11-S14; Neculae G et al. ESC Heart Fail, 2024 Oct;11:2825-2834). This variant was reported to segregate with disease in a family with Müller cell dystrophy (Dalma-Weiszhausz J et al. Retina, 2022 May;42:981-991). Two other variants at the same codon, p.E109Q (c.325G>C) and p.E109K (c.325G>A), have also been detected in individuals with TTR amyloidosis (Barreiros AP et al. Liver Transpl., 2010 Mar;16:314-23; Coelho T et al. Curr Med Res Opin. 2013;29(1):63-76; Rapezzi C. et al. Eur Heart J. 2013;34(7):520-8, Castaño A, et al. Heart Fail Rev 2015 Mar; 20(2):163-78). 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. |