NM_198253.3(TERT):c.2177C>T (p.Thr726Met) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 24, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001818203.11

Allele description [Variation Report for NM_198253.3(TERT):c.2177C>T (p.Thr726Met)]

NM_198253.3(TERT):c.2177C>T (p.Thr726Met)

Gene:

TERT:telomerase reverse transcriptase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5p15.33

Genomic location:

Preferred name:

NM_198253.3(TERT):c.2177C>T (p.Thr726Met)

HGVS:

NC_000005.10:g.1278750G>A
NG_009265.1:g.21298C>T
NM_001193376.3:c.2177C>T
NM_198253.3:c.2177C>TMANE SELECT
NP_001180305.1:p.Thr726Met
NP_937983.2:p.Thr726Met
NP_937983.2:p.Thr726Met
LRG_343t1:c.2177C>T
LRG_343:g.21298C>T
LRG_343p1:p.Thr726Met
NC_000005.9:g.1278865G>A
NM_198253.2:c.2177C>T
NR_149162.3:n.2256C>T
NR_149163.3:n.2220C>T
O14746:p.Thr726Met

Protein change:

T726M

Links:

UniProtKB: O14746#VAR_062539; dbSNP: rs149566858

NCBI 1000 Genomes Browser:

rs149566858

Molecular consequence:

NM_001193376.3:c.2177C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198253.3:c.2177C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_149162.3:n.2256C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_149163.3:n.2220C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002068059	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 24, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002068059

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 24, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV002068059.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

DNA sequence analysis of the TERT gene demonstrated a sequence change, c.2177C>T, in exon 6 that results in an amino acid change, p.Thr726Met. This sequence change has been described in the gnomAD database with a frequency of 0.01% in the European sub-population (dbSNP rs149566858). The p.Thr726Met change has been reported in individuals with aplastic anemia, dyskeratosis congenita, Hoyeraal Hreidarsson syndrome, and emphysema (PMID: 16627250, 25562321, 23538340, 26329388). This sequence change has also been identified in the unaffected parent of an individual with aplastic anemia (PMID: 16627250). The p.Thr726Met change affects a poorly conserved amino acid residue located in a domain of the TERT protein that is known to be functional. The p.Thr726Met substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Some studies have demonstrated that the p.Thr726Met change does not significantly impact telomerase enzyme activity (PMID: 26887940, 23901009, 16990594), while others have reported impaired enzyme activity in presence of this variant (PMID: 25562321, 28813500). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr726Met change remains unknown at this time.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 1, 2024

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