Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000036378 | SCV000060033 | uncertain significance | not specified | 2012-07-31 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Benign. The Thr23Met varian t in TTR has not been reported in the literature nor previously identified by ou r laboratory. Threonine (Thr) at position 23 is not conserved in evolution, sugg esting that a change at this position may be tolerated. Computational analyses ( biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) also suggest that this variant may not impact the protein. This variant is located in the las t three bases of the exon, which is part of the 5' splice region, but computatio nal tools do not predict altered splicing (the accuracy of these tools is unknow n). The lack of amino acid conservation suggests that the Tyr535His variant may be benign, but additional studies are needed to establish this with confidence. |
| Gene |
RCV001719730 | SCV000209361 | uncertain significance | not provided | 2019-12-17 | criteria provided, single submitter | clinical testing | Has not been previously published in association with TTR-related disorders to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 663602; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30683924) |
| Labcorp Genetics |
RCV001071114 | SCV001236401 | uncertain significance | Amyloidosis, hereditary systemic 1 | 2023-12-11 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 23 of the TTR protein (p.Thr23Met). This variant is present in population databases (rs377052919, gnomAD 0.007%). 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: 43456). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Fulgent Genetics, |
RCV002482975 | SCV002790378 | uncertain significance | Hyperthyroxinemia, dystransthyretinemic; Amyloidosis, hereditary systemic 1; Carpal tunnel syndrome 1 | 2024-06-04 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV004018793 | SCV004973495 | uncertain significance | Cardiovascular phenotype | 2022-04-18 | criteria provided, single submitter | clinical testing | The c.68C>T (p.T23M) alteration is located in exon 1 (coding exon 1) of the TTR gene. This alteration results from a C to T substitution at nucleotide position 68, causing the threonine (T) at amino acid position 23 to be replaced by a methionine (M). The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.68C>T alteration was observed in 0.002% (6/251,332) of total alleles studied. The altered amino acid is not conserved throughout evolution:_x000D_ _x000D_ The p.T23 amino acid is not conserved in available vertebrate species. The alteration is predicted benign by in silico models:_x000D_ _x000D_ The p.T23M alteration is predicted to be benign by Polyphen and tolerated by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |