Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001054625 | SCV001218971 | likely pathogenic | Familial amyloid neuropathy | 2019-12-05 | criteria provided, single submitter | clinical testing | 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.Ala65 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7599630, 23713495, 24953234, 28460244, 10842718). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). This variant has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 1570831, 31139689). This variant is also known as Ala45Thr in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 65 of the TTR protein (p.Ala65Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. |
| Athena Diagnostics | RCV001288932 | SCV001476390 | likely pathogenic | not provided | 2019-11-15 | criteria provided, single submitter | clinical testing | Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. |
| Ambry Genetics | RCV002409453 | SCV002723935 | pathogenic | Cardiovascular phenotype | 2022-08-10 | criteria provided, single submitter | clinical testing | The p.A65T pathogenic mutation (also known as c.193G>A), located in coding exon 2 of the TTR gene, results from a G to A substitution at nucleotide position 193. The alanine at codon 65 is replaced by threonine, an amino acid with similar properties. This alteration has been reported (often with nomenclature p.A45T) in individuals with hereditary transthyretin amyloidosis (hATTR) (Saraiva MJ et al. Am. J. Hum. Genet., 1992 May;50:1027-30; Cortese A et al. J. Neurol., 2016 May;263:916-924; Chao HC et al. Ann Clin Transl Neurol, 2019 May;6:913-922). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Zanotti G et al. Eur. J. Biochem., 1995 Dec;234:563-9; Ambry internal data). Other alterations impacting the same codon (p.A65V, p.A65G, p.A65S, and p.A65D) have also been described in association with hATTR (Saraiva MJ et al. Am. J. Hum. Genet. 1992 May;50:1027-30; Janunger T et al. Amyloid. 2000 Jun;7(2):137-40; Adams D et al. Neurology, 2015 Aug;85:675-82; Pilebro B et al. Ups. J. Med. Sci. 2016 Feb;121:17-24). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |