ClinVar Miner

Submissions for variant NM_198253.3(TERT):c.1892G>A (p.Arg631Gln)

dbSNP: rs199422294
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Degerman lab, Umeå University 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
GeneReviews RCV000032370 SCV000056026 not provided Interstitial lung disease 2 no assertion provided literature only
Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology RCV000032370 SCV000803359 pathogenic Interstitial lung disease 2 2018-05-06 no assertion criteria provided case-control
Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center 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, University of Chicago 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, Johns Hopkins University School of Medicine RCV003325404 SCV003840217 pathogenic Telomere syndrome 2022-08-01 no assertion criteria provided clinical testing

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