5-1280216-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_198253.3(TERT):c.1892G>A(p.Arg631Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R631W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 4.14

Genes affected

TERT (HGNC:11730): (telomerase reverse transcriptase) Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. The enzyme consists of a protein component with reverse transcriptase activity, encoded by this gene, and an RNA component which serves as a template for the telomere repeat. Telomerase expression plays a role in cellular senescence, as it is normally repressed in postnatal somatic cells resulting in progressive shortening of telomeres. Deregulation of telomerase expression in somatic cells may be involved in oncogenesis. Studies in mouse suggest that telomerase also participates in chromosomal repair, since de novo synthesis of telomere repeats may occur at double-stranded breaks. Alternatively spliced variants encoding different isoforms of telomerase reverse transcriptase have been identified; the full-length sequence of some variants has not been determined. Alternative splicing at this locus is thought to be one mechanism of regulation of telomerase activity. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-1280217-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 916675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 5-1280216-C-T is Pathogenic according to our data. Variant chr5-1280216-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 29899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-1280216-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.1892G>A	p.Arg631Gln	missense_variant	4/16	ENST00000310581.10
TERT	NM_001193376.3	c.1892G>A	p.Arg631Gln	missense_variant	4/15
TERT	NR_149162.3	n.1971G>A		non_coding_transcript_exon_variant	4/13
TERT	NR_149163.3	n.1971G>A		non_coding_transcript_exon_variant	4/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.1892G>A	p.Arg631Gln	missense_variant	4/16	1	NM_198253.3	P2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Interstitial lung disease 2 Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	case-control	Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology	May 06, 2018	- -

Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 15, 2023

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). -

Hereditary cancer-predisposing syndrome;C0265965:Dyskeratosis congenita Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2022

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. -

Telomere syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

The Telomere Center at Johns Hopkins, Johns Hopkins University School of Medicine

Aug 01, 2022

- -

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Degerman lab, Umeå University

Nov 23, 2017

- -

Pulmonary fibrosis Pathogenic:1

Likely risk allele, no assertion criteria provided

research

Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center

Jun 09, 2022

Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted -

Dyskeratosis congenita, autosomal dominant 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2008

- -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

May 04, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.92		Loss of MoRF binding (P = 0.0317);Loss of MoRF binding (P = 0.0317);
MVP		1.0
MPC		2.3
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.76
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199422294; hg19: chr5-1280331;