Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000700173 | SCV000828918 | pathogenic | Familial amyloid neuropathy | 2024-01-20 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 80 of the TTR protein (p.Thr80Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (Invitae). ClinVar contains an entry for this variant (Variation ID: 577420). 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.Thr80 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 3722385, 12050338, 15820680, 21992998, 25997029, 26017327). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| ARUP Laboratories, |
RCV000756862 | SCV000884820 | likely pathogenic | not provided | 2018-01-21 | criteria provided, single submitter | clinical testing | The TTR c.239C>T; p.Thr80Ile variant is not reported in the literature and is absent from the general population (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. A different missense variant at codon 80 (Thr80Ala) has been reported in multiple unrelated patients with familial amyloidotic polyneuropathy (FAP) (Wallace 1986, Sattianayagam 2012) and is frequently associated with cardiac amyloidosis. Both p.Thr80Ala and p.Thr80Ile substitute the native uncharged polar residue with a nonpolar residue. The threonine at codon 80 is moderately conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging. Based on the above information, this variant is considered likely pathogenic. References: Wallace M et al. Biochemical and molecular genetic characterization of a new variant prealbumin associated with hereditary amyloidosis. J Clin Invest. 1986 Jul; 78(1): 6–12. Sattianayagam P et al. Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant. Eur Heart J. 2012 May;33(9):1120-7. |
| Ambry Genetics | RCV002458280 | SCV002738512 | likely pathogenic | Cardiovascular phenotype | 2023-12-13 | criteria provided, single submitter | clinical testing | The p.T80I variant (also known as c.239C>T), located in coding exon 3 of the TTR gene, results from a C to T substitution at nucleotide position 239. The threonine at codon 80 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported in multiple patients with transthyretin (ATTR) amyloidosis (Ambry internal data; external communication; Chaudhary AG et al. CJC Open, 2022 Dec;4:1031-1035). This variant was also described in a Saudi exome cohort; however, clinical details were limited (Abouelhoda M et al. Hum Genomics, 2021 Aug;15:52). An alternate amino acid substitution at this position, p.T80A (historically described as p.T60A), has been detected in numerous individuals with ATTR amyloidosis and is associated with cardiac symptoms (Wallace MR et al. J. Clin. Invest., 1986 Jul;78:6-12; Zeldenrust SR. Amyloid, 2012 Jun;19 Suppl 1:22-4; Ihse E et al. Amyloid, 2013 Sep;20:142-50; Swiecicki PL et al. Amyloid, 2015 May;22:123-31). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Athena Diagnostics | RCV000756862 | SCV002771674 | likely pathogenic | not provided | 2021-06-09 | criteria provided, single submitter | clinical testing | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Computational tools predict that this variant is damaging. |
| Center for Genomic Medicine, |
RCV000700173 | SCV004808023 | uncertain significance | Familial amyloid neuropathy | 2024-03-29 | criteria provided, single submitter | clinical testing | |
| Neuberg Centre For Genomic Medicine, |
RCV000700173 | SCV005044765 | likely pathogenic | Familial amyloid neuropathy | criteria provided, single submitter | clinical testing | The missense c.239C>Tp.Thr80Ile variant in TTR gene has been reported in heterozygous state in individuals affected withtransthyretin amyloidosis Abouelhoda M, et. al., 2021; Chaudhary AG, et. al., 2022. The p.Thr80Ile variant is novel not in anyindividuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likelypathogenic multiple submissions. The amino acid change p.Thr80Ile in TTR is predicted as conserved by GERP++ and PhyloPacross 100 vertebrates. The amino acid Thr at position 80 is changed to a Ile changing protein sequence and it might alter itscomposition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic. |