Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Degerman lab, |
RCV000677344 | SCV000611696 | pathogenic | Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 | 2017-11-23 | criteria provided, single submitter | clinical testing | |
Invitae | RCV002513175 | SCV002228882 | pathogenic | Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis | 2023-05-15 | criteria provided, single submitter | clinical testing | Experimental studies have shown that this missense change affects TERT function (PMID: 19760749, 26024875). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 29899). This missense change has been observed in individual(s) with clinical features of TERT-related conditions (PMID: 18460650, 19760749, 22853774, 26024875, 29483670). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 631 of the TERT protein (p.Arg631Gln). |
Ambry Genetics | RCV002408477 | SCV002719436 | pathogenic | Dyskeratosis congenita; Hereditary cancer-predisposing syndrome | 2022-11-10 | criteria provided, single submitter | clinical testing | The p.R631Q pathogenic mutation (also known as c.1892G>A), located in coding exon 4 of the TERT gene, results from a G to A substitution at nucleotide position 1892. The arginine at codon 631 is replaced by glutamine, an amino acid with highly similar properties. This mutation has been reported in multiple families with idiopathic pulmonary fibrosis or dyskeratosis congenita (Basel-Vanagaite L, et al. Haematologica. 2008 Jun; 93(6):943-4; Kirwan M, et al. Br. J. Haematol. 2008 Mar; 140(6):719-22; Kirwan M, et al. Hum. Mutat. 2009 Nov; 30(11):1567-73; Diaz de Leon A, et al. PLoS ONE. 2010 May; 5(5):e10680; Fernandez BA, et al. Respir. Res. 2012 ; 13():64; Collopy LC, et al. Blood. 2015 Jul; 126(2):176-84). Functional analysis in several studies demonstrated that this mutation severely reduced telomerase activity (Kirwan M, et al. Hum. Mutat. 2009 Nov; 30(11):1567-73;Diaz de Leon A, et al. PLoS ONE. 2010 May; 5(5):e10680; Collopy LC, et al. Blood. 2015 Jul; 126(2):176-84). In addition, this variant was shown to segregate with disease in a family in which the proband was shown to have short telomere length relative to controls (Norberg A et al. Eur. J. Hum. Genet., 2018 06;26:858-867). Based on the supporting evidence, p.R631Q is interpreted as a disease-causing mutation. |
OMIM | RCV000022783 | SCV000044072 | pathogenic | Dyskeratosis congenita, autosomal dominant 2 | 2008-06-01 | no assertion criteria provided | literature only | |
Gene |
RCV000032370 | SCV000056026 | not provided | Interstitial lung disease 2 | no assertion provided | literature only | ||
Department of Respiratory and Critical Care Medicine, |
RCV000032370 | SCV000803359 | pathogenic | Interstitial lung disease 2 | 2018-05-06 | no assertion criteria provided | case-control | |
Garcia Pulmonary Genetics Research Laboratory, |
RCV002509167 | SCV002547410 | likely risk allele | Pulmonary fibrosis | 2022-06-09 | no assertion criteria provided | research | Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted |
Genetic Services Laboratory, |
RCV003150932 | SCV003840115 | pathogenic | not provided | 2022-05-04 | no assertion criteria provided | clinical testing | DNA sequence analysis of the TERT gene demonstrated a sequence change, c.1892G>A, in exon 4 that results in an amino acid change, p.Arg631Gln. The p.Arg631Gln change affects a highly conserved amino acid residue located in a domain of the TERT protein that is known to be functional. The p.Arg631Gln substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Experimental studies have demonstrated that this sequence change impacts the function of the TERT protein (PMID: 26024875, 19760749). This sequence change has previously been described in multiple individuals with TERT-related disorders (PMID: 29920840, 22853774, 19760749, 18460650, 26024875, 29483670). This sequence change has not been described in population databases such as ExAC and gnomAD. The p.Arg631Gln amino acid change occurs in a region of the TERT gene where other missense sequence changes have been described in individuals with TERT-related disorders including another missense change at the same position (p. Arg631Trp) (PMID: 26859482, 26329388, 30523342). Collectively, these evidences indicate this sequence change is pathogenic. |
The Telomere Center at Johns Hopkins, |
RCV003325404 | SCV003840217 | pathogenic | Telomere syndrome | 2022-08-01 | no assertion criteria provided | clinical testing |