Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute of Medical Genetics and Applied Genomics, |
RCV001268086 | SCV001446732 | likely pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002541635 | SCV002176271 | uncertain significance | Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis | 2021-10-15 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with cysteine at codon 865 of the TERT protein (p.Arg865Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This missense change has been observed in individual(s) with idiopathic pulmonary fibrosis (IPF) (PMID: 17460043, 20502709). ClinVar contains an entry for this variant (Variation ID: 986922). 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 TERT protein function. Experimental studies have shown that this missense change affects TERT function (PMID: 22364217). This variant disrupts the p.Arg865 amino acid residue in TERT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17460043, 22853774, 28102861, 30523342). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |
| Ambry Genetics | RCV002451631 | SCV002739391 | likely pathogenic | Dyskeratosis congenita; Hereditary cancer-predisposing syndrome | 2018-12-22 | criteria provided, single submitter | clinical testing | The p.R865C variant (also known as c.2593C>T), located in coding exon 10 of the TERT gene, results from a C to T substitution at nucleotide position 2593. The arginine at codon 865 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in an individual with pulmonary fibrosis, neutropenia, and shortened telomere length (Tsakiri KD et al. Proc. Natl. Acad. Sci. U.S.A., 2007 May;104:7552-7; Diaz de Leon A et al. PLoS ONE, 2010 May;5:e10680; Newton CA et al. Eur. Respir. J., 2016 12;48:1710-1720). Telomerase activity analysis in vitro and in human cells demonstrated a reduced activity compared to wild type (Tsang AR et al. Aging Cell, 2012 Jun;11:482-90). A disease-causing mutation, p.R865H, has been described in the same codon (Tsakiri KD et al. Proc. Natl. Acad. Sci. U.S.A., 2007 May;104:7552-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |