5-1280216-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 4.14

Publications

18 publications found

Variant links:

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]

TERT Gene-Disease associations (from GenCC):

pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
dyskeratosis congenita, autosomal dominant 2
Inheritance: AR, AD, SD, Unknown Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine
acute myeloid leukemia
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
dyskeratosis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hoyeraal-Hreidarsson syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
melanoma, cutaneous malignant, susceptibility to, 9
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

TERT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId 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 VariationId is 29899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3 link	c.1892G>A	p.Arg631Gln	missense_variant	Exon 4 of 16	ENST00000310581.10	NP_937983.2	O14746-1
TERT	NM_001193376.3 link	c.1892G>A	p.Arg631Gln	missense_variant	Exon 4 of 15		NP_001180305.1	O14746-3
TERT	NR_149162.3 link	n.1971G>A		non_coding_transcript_exon_variant	Exon 4 of 13
TERT	NR_149163.3 link	n.1971G>A		non_coding_transcript_exon_variant	Exon 4 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10 link	c.1892G>A	p.Arg631Gln	missense_variant	Exon 4 of 16	1	NM_198253.3	ENSP00000309572.5		O14746-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dyskeratosis congenita, autosomal dominant 2

Pathogenic:3

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant c.1892G>A(p.Arg631Gln) in TERT gene has been observed in heterozygous and/or compound heterozygous state in individual(s) with clinical features of TERT-related conditions (Collopy LC et. al.,; 2015; Norberg A et. al., 2018). It has also been observed to segregate with disease in related individuals. Experimental studies have shown that this missense change affects TERT function (Collopy LC et. al.,; 2015). The observed variant is absent in gnomAD exomes database. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. Multiple lines of computational evidence (Polyphen - probably damaging, SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid change p.Arg631Gln in TERT is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 631 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Jun 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jun 08, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000029899 /PMID: 18460650). A different missense change at the same codon (p.Arg631Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000916675 /PMID: 26859482). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:2

May 04, 2022

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method: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. -

Feb 08, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: decreased TERT protein expression and negligible telomerase activity with correspondingly short telomeres (PMID: 26024875, 20502709, 19760749); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20301779, 20502709, 19760749, 18460650, 26024875, 22853774, 23716176, 29483670, 18302718) -

Interstitial lung disease 2

Pathogenic:1Other:1

May 06, 2018

Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:case-control

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

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

Pathogenic:1

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 29899). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TERT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TERT function (PMID: 19760749, 26024875). For these reasons, this variant has been classified as Pathogenic. -

Telomere syndrome

Pathogenic:1

Aug 01, 2022

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

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Pulmonary fibrosis

Pathogenic:1

Jun 09, 2022

Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center

Significance:Likely risk allele

Review Status:no assertion criteria provided

Collection Method:research

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

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

Pathogenic:1

Nov 23, 2017

Degerman lab, Umeå University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dyskeratosis congenita

Pathogenic:1

Nov 10, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;M

PhyloP100

4.1

PrimateAI

Benign

0.45

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

GERP RS

4.5

Varity_R

0.76

gMVP

1.0

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over