VCV001695952.3 - ClinVar

NM_198253.3(TERT):c.2398G>A (p.Glu800Lys)

Germline

Classification

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.

(3)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_198253.3(TERT):c.2398G>A (p.Glu800Lys)

Variation ID: 1695952 Accession: VCV001695952.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5p15.33 5: 1271189 (GRCh38) [ NCBI UCSC ] 5: 1271304 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Jan 15, 2023	Feb 28, 2024	Nov 19, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_198253.3:c.2398G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_937983.2:p.Glu800Lys	missense
NM_001193376.3:c.2398G>A	NP_001180305.1:p.Glu800Lys	missense
NC_000005.10:g.1271189C>T
NC_000005.9:g.1271304C>T
NG_009265.1:g.28859G>A
LRG_343:g.28859G>A

... more HGVS ... less HGVS

Protein change

E800K

Other names

p.Glu800Lys

Canonical SPDI

NC_000005.10:1271188:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help 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.
TERT		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2985	3428

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help 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.
Pulmonary fibrosis	Likely risk allele (1)	no assertion criteria provided	Jun 9, 2022	RCV002509803.1
Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1	Uncertain significance (1)	criteria provided, single submitter	Apr 12, 2021	RCV003456282.1
Dyskeratosis congenita, autosomal dominant 2 Idiopathic Pulmonary Fibrosis	Uncertain significance (1)	criteria provided, single submitter	Nov 19, 2022	RCV003774840.2

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.
Uncertain significance (Apr 12, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center Accession: SCV004190157.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: The c. 2398G>A variant in the TERT gene is a heterozygous missense variant, which results in the substitution of the highly conserved glutamate residue at … (more) The c. 2398G>A variant in the TERT gene is a heterozygous missense variant, which results in the substitution of the highly conserved glutamate residue at the 800 position to lysine (p.Glu800Lys). This variant localizes to coding exon 8 of the gene (16 exons total; NM_198253.3) and is within the reverse transcriptase domain of the protein. Predictions of the effect of this variant on protein structure and/or function based on in-silico analyses are inconsistent. This variant is absent in the Genome Aggregation Database (gnomAD), indicating it is not a common benign variant in the populations represented in this database. To the best of our knowledge, this specific variant has not been described in the literature or any human disease variant databases to be associated with disease. (less) Clinical Features: Pulmonary fibrosis (present) Age: 60-69 years Sex: male
Uncertain significance (Nov 19, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	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	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004591641.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Comment: This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 800 of the TERT protein … (more) This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 800 of the TERT protein (p.Glu800Lys). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. This variant has not been reported in the literature in individuals affected with TERT-related conditions. This variant is not present in population databases (gnomAD no frequency). (less)
Likely risk allele (Jun 09, 2022)	no assertion criteria provided Method: research	Pulmonary fibrosis Affected status: yes Allele origin: germline	Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center Accession: SCV002547400.1 First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023

Comment:

The c. 2398G>A variant in the TERT gene is a heterozygous missense variant, which results in the substitution of the highly conserved glutamate residue at the 800 position to lysine (p.Glu800Lys). This variant localizes to coding exon 8 of the gene (16 exons total; NM_198253.3) and is within the reverse transcriptase domain of the protein. Predictions of the effect of this variant on protein structure and/or function based on in-silico analyses are inconsistent. This variant is absent in the Genome Aggregation Database (gnomAD), indicating it is not a common benign variant in the populations represented in this database. To the best of our knowledge, this specific variant has not been described in the literature or any human disease variant databases to be associated with disease.

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 800 of the TERT protein (p.Glu800Lys). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. This variant has not been reported in the literature in individuals affected with TERT-related conditions. This variant is not present in population databases (gnomAD no frequency).

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.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_198253.3(TERT):c.2398G>A (p.Glu800Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...