ClinVar Genomic variation as it relates to human health
NM_198253.3(TERT):c.1317GGA[2] (p.Glu441del)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(3); Benign(1); Likely benign(11)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_198253.3(TERT):c.1317GGA[2] (p.Glu441del)
Variation ID: 212398 Accession: VCV000212398.48
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 5p15.33 5: 1293561-1293563 (GRCh38) [ NCBI UCSC ] 5: 1293676-1293678 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 5, 2015 Apr 15, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_198253.3:c.1317GGA[2] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_937983.2:p.Glu441del inframe deletion NM_198253.3:c.1317_1319GGA[2] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_937983.2:p.Glu441del inframe deletion NM_001193376.3:c.1317GGA[2] NP_001180305.1:p.Glu441del inframe deletion NM_198253.2:c.1323_1325delGGA NR_149162.3:n.1396GGA[2] non-coding transcript variant NR_149163.3:n.1396GGA[2] non-coding transcript variant NC_000005.10:g.1293563CTC[2] NC_000005.9:g.1293678CTC[2] NG_009265.1:g.6479GGA[2] LRG_343:g.6479GGA[2] - Protein change
- E441del
- Other names
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- Canonical SPDI
- NC_000005.10:1293560:TCCTCCTCCTC:TCCTCCTC
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00080 (TCCTCCTC)
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TERT | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2810 | 3231 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Mar 22, 2018 | RCV000192469.20 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000275900.13 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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May 28, 2019 | RCV000312359.14 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000370254.13 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Mar 1, 2024 | RCV000726693.32 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 30, 2021 | RCV000768107.10 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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May 18, 2021 | RCV001261857.10 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001843492.9 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV002517983.9 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 1, 2023 | RCV003917777.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely benign
(Mar 13, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000249151.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Interstitial lung disease 2
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001136806.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(May 18, 2021)
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criteria provided, single submitter
Method: curation
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Dyskeratosis congenita
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002533101.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Dyskeratosis congenita, autosomal dominant 2
Idiopathic Pulmonary Fibrosis
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000291846.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
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Likely benign
(Mar 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001748114.14
First in ClinVar: Jul 10, 2021 Last updated: Apr 15, 2024 |
Comment:
TERT: BP3, BS1
Number of individuals with the variant: 12
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Aplastic Anemia
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000452691.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Dyskeratosis Congenita, Recessive
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000452692.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Familial Pulmonary Fibrosis
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000452693.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Uncertain significance
(Oct 26, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000702135.2
First in ClinVar: May 29, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Likely benign
(Mar 22, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000272498.3
First in ClinVar: May 29, 2016 Last updated: Aug 26, 2019 |
Comment:
p.Glu441del in exon 2 of TERT: This variant is classified as likely benign becau se it has been identified in 0.4% (248/68934) of European chromosomes … (more)
p.Glu441del in exon 2 of TERT: This variant is classified as likely benign becau se it has been identified in 0.4% (248/68934) of European chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs3776 39087). Of note, gibbons have a deletion at this position despite high nearby am ino acid conservation. In addition, although this variant has been reported in s everal studies in individuals with TERT-related conditions, many of these studie s consider the variant to be a polymorphism and the functional evidence availabl e suggests this variant does not have a significant impact on telomere length (Y amaguchi 2005, Calado 2009, Calado 2011, Kirwan 2009, Calado 2011, Fernandez 201 2, Zaug 2013, Maxwell 2016). ACMG/AMP Criteria applied: BS1; BS3_Supporting. (less)
Number of individuals with the variant: 2
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Likely benign
(Sep 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Dyskeratosis congenita
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV001439199.1
First in ClinVar: Oct 25, 2020 Last updated: Oct 25, 2020 |
Comment:
The p.Glu441del frameshift variant has a frequency of 0.001719 (311 of 180,940 alleles) in gnomAD v2.1.1 with a maximal allele frequency of 0.003621 (261 of … (more)
The p.Glu441del frameshift variant has a frequency of 0.001719 (311 of 180,940 alleles) in gnomAD v2.1.1 with a maximal allele frequency of 0.003621 (261 of 72,072) in the European non-Finnish subpopulation (http://gnomad.broadinstitute.org). Pathogenic variants in the TERT gene predispose individuals to dyskeratosis congenita (DKC). While the exact prevalence of DKC is unknown, it is estimated to occur in approximately 1 in 1 million people. Therefore, the population frequency is not consistent with disease (BS1). This variant has been reported as heterozygous in an individual with aplastic anemia (PMID: 19674077) and as homozygous in an individual with acute myeloid leukemia (PMID: 19147845). The variant represents an in-frame deletion of 1 glutamic acid residue in a repeat of 3 glutamic acid residues (BP3). Results of telomerase activity assays have been conflicting. In several reports, the E441del variant has similar activity to the wild-type allele (PMID: 15814878, 23901009), however another report demonstrated approximately 40% of functional activity as compared to the wild-type allele (PMID: 19147845). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP3. (less)
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Likely benign
(Dec 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000565612.6
First in ClinVar: May 29, 2016 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 27153395, 22853774, 21520173, 23901009, 19147845, 19674077, 19760749, 15814878, 28951115)
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Uncertain significance
(Mar 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Dyskeratosis congenita, autosomal dominant 2
Dyskeratosis congenita, autosomal dominant 2 Melanoma, cutaneous malignant, susceptibility to, 9 Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 Acute myeloid leukemia
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV000899022.2
First in ClinVar: Apr 25, 2019 Last updated: May 20, 2023 |
Comment:
TERT NM_198253.2 exon 2 p.Glu441del (c.1323_1325del): This variant has been reported in the literature as heterozygous in at 2 least individuals with varying phenotypes (hepatic … (more)
TERT NM_198253.2 exon 2 p.Glu441del (c.1323_1325del): This variant has been reported in the literature as heterozygous in at 2 least individuals with varying phenotypes (hepatic cirrhosis, aplastic anemia) as well as homozygous in 1 individual with acute myelogenous leukemia (AML) (Yamaguchi 2005 PMID:15814878, Calado 2009 PMID:19674077, Calado 2009 PMID:19147845, Calado 2011 PMIDL21520173). The interpretation of this variant in the current literature is unclear, with at least 2 publications calling this variant a polymorphism (Yamaguchi 2005 PMID:15814878, Maxwell 2016 PMID:27153395). Functional studies are also conflicting, suggesting either a 40% reduction (compared to WT) to near normal effect of this variant on telomerase enzyme activity (Calado 2009 PMID:19147845, Zaug 2013 PMID:23901009). This variant is also present in 0.3% (248/68934) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/5-1293675-GTCC-G). This variant is present in ClinVar, with discrepant classifications ranging from likely benign to variant of uncertain significance (Variation ID:212398).This variant represents an in-frame deletion of 1 glutamic acid residue in a repeat of 3 glutamic acids. This is not predicted to alter the reading frame, but the ultimate effect of this variant on the protein is unclear. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010201.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Likely benign
(Jun 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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TERT-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004734438.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Hepatoblastoma
Affected status: yes
Allele origin:
germline
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Molecular Oncology - Human Genetics Lab, University of Sao Paulo
Accession: SCV002103148.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001554358.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The TERT p.Glu441del variant was identified in the literature in two patients with aplastic anemia, a patient with acute myeloid leukemia and another patient with … (more)
The TERT p.Glu441del variant was identified in the literature in two patients with aplastic anemia, a patient with acute myeloid leukemia and another patient with cirrhosis caused by alcohol (Yamaguchi_2005_PMID:15814878; Calado_2009_PMID:19674077; Calado_2009_PMID:19147845; Calado_2011_PMID:21520173). The variant was identified in dbSNP (ID: rs377639087), Cosmic, LOVD 3.0 and ClinVar (classified as likely benign by GeneDx, Invitae, Laboratory for Molecular Medicine, Illumina and Genetic Services Laboratory, University of Chicago and as uncertain significance by EGL Genetics and Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago). The variant was identified in control databases in 311 of 180940 chromosomes at a frequency of 0.001719 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 261 of 72072 chromosomes (freq: 0.003621), Other in 14 of 5334 chromosomes (freq: 0.002625), Ashkenazi Jewish in 9 of 8490 chromosomes (freq: 0.00106), European (Finnish) in 10 of 18616 chromosomes (freq: 0.000537), Latino in 11 of 25422 chromosomes (freq: 0.000433), African in 5 of 15812 chromosomes (freq: 0.000316) and South Asian in 1 of 22778 chromosomes (freq: 0.000044), but was not observed in the East Asian population. This variant is an in-frame deletion resulting in the removal of a glutamic acid (glu) residue at codon 441; the impact of this alteration on TERT protein function is not known. Functional studies have shown no association with telomere shortening but a decrease in telomere activity has been reported (Yamaguchi_2005_PMID:15814878; Calado_2009_PMID:19147845). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
Many disease-associated variants of hTERT retain high telomerase enzymatic activity. | Zaug AJ | Nucleic acids research | 2013 | PMID: 23901009 |
A Newfoundland cohort of familial and sporadic idiopathic pulmonary fibrosis patients: clinical and genetic features. | Fernandez BA | Respiratory research | 2012 | PMID: 22853774 |
Constitutional telomerase mutations are genetic risk factors for cirrhosis. | Calado RT | Hepatology (Baltimore, Md.) | 2011 | PMID: 21520173 |
Defining the pathogenic role of telomerase mutations in myelodysplastic syndrome and acute myeloid leukemia. | Kirwan M | Human mutation | 2009 | PMID: 19760749 |
Erosion of telomeric single-stranded overhang in patients with aplastic anaemia carrying telomerase complex mutations. | Calado RT | European journal of clinical investigation | 2009 | PMID: 19674077 |
Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia. | Calado RT | Proceedings of the National Academy of Sciences of the United States of America | 2009 | PMID: 19147845 |
Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. | Yamaguchi H | The New England journal of medicine | 2005 | PMID: 15814878 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TERT | - | - | - | - |
Text-mined citations for rs377639087 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.