Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001386305 | SCV001586491 | pathogenic | Familial amyloid neuropathy | 2023-06-09 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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, 28635949). 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. ClinVar contains an entry for this variant (Variation ID: 1073324). This variant is also known as Glu89Lys. This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 10842705, 20209591, 25644864, 26428663, 28911993). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 109 of the TTR protein (p.Glu109Lys). |
| ARUP Laboratories, |
RCV001530146 | SCV002049657 | likely pathogenic | not provided | 2021-11-02 | criteria provided, single submitter | clinical testing | The TTR c.325G>A; p.Glu109Lys variant, also known as p.Glu89Lys, is reported in the literature in multiple individuals affected with hereditary transthyretin amyloidosis (ATTR, Nakamura 2000, Reynolds 2017, Rapezzi 2013, Suhr 2016). This variant is also reported in ClinVar (Variation ID: 1073324) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other variants at this codon (c.325G>C, p.Glu109Lys; c.327G>T, p.Glu109Asp) have been reported in individuals with ATTR and are considered pathogenic (Chao 2019, Reynolds 2017). The glutamic acid at codon 109 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.767). Based on available information, this variant is considered to be likely pathogenic. References: Chao HC et al. Clinical and genetic profiles of hereditary transthyretin amyloidosis in Taiwan. Ann Clin Transl Neurol. 2019 Apr 9;6(5):913-922. PMID: 31139689. Nakamura M et al. A novel variant of transthyretin (Glu89Lys) associated with familial amyloidotic polyneuropathy. Amyloid. 2000 Mar;7(1):46-50. PMID: 10842705. Reynolds MM et al. Ocular Manifestations of Familial Transthyretin Amyloidosis. Am J Ophthalmol. 2017 Nov;183:156-162. PMID: 28911993. Rapezzi C et al. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur Heart J. 2013 Feb;34(7):520-8. PMID: 22745357. Suhr OB et al. Survival After Transplantation in Patients With Mutations Other Than Val30Met: Extracts From the FAP World Transplant Registry. Transplantation. 2016 Feb;100(2):373-81. PMID: 26656838. |
| Mendelics | RCV001386305 | SCV002519922 | pathogenic | Familial amyloid neuropathy | 2022-05-04 | criteria provided, single submitter | clinical testing | |
| 3billion | RCV001386305 | SCV002573141 | pathogenic | Familial amyloid neuropathy | 2022-09-01 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.77; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV001073324 ) and a different missense change at the same codon (p.Glu109Gln / ClinVar ID: VCV000013442 ) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |
| Ambry Genetics | RCV002322365 | SCV002606912 | pathogenic | Cardiovascular phenotype | 2021-01-21 | criteria provided, single submitter | clinical testing | The p.E109K pathogenic mutation (also known as c.325G>A), located in coding exon 3 of the TTR gene, results from a G to A substitution at nucleotide position 325. The glutamic acid at codon 109 is replaced by lysine, an amino acid with similar properties. This mutation (also referred to as and E89K) has been detected in several individuals from hereditary transthyretin amyloidosis and familial amyloid polyneuropathy cohorts including individuals with polyneuropathy, cardiac involvement or mixed phenotype (Barreiros AP, et al. Liver Transpl. 2010;16(3):314-23; Rapezzi C, et al. Eur. Heart J. 2013;34(7):520-8; Choi K et al. J Clin Neurol. 2018 Oct;14(4):537-541; Gawor M et al. Cardiol J, 2020 Aug [online ahead of print]). This mutation was also reported to segregate with disease in a family (Jang MA et al. Ann Hum Genet, 2015 Mar;79:99-107). In addition, another mutation at the same position (p.E109Q, c.325G>C) has also been reported in association with hereditary transthyretin amyloidosis (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). This variant was not reported in population-based 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. |
| Diagnostic Laboratory, |
RCV001530146 | SCV001744868 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV001530146 | SCV001973308 | likely pathogenic | not provided | no assertion criteria provided | clinical testing |