Submissions for variant NM_198253.3(TERT):c.3329C>T (p.Thr1110Met)

gnomAD frequency: 0.00004  dbSNP: rs199422306

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514134	SCV000551508	uncertain significance	Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1110 of the TERT protein (p.Thr1110Met). This variant is present in population databases (rs199422306, gnomAD 0.01%). This missense change has been observed in individual(s) with idiopathic pulmonary fibrosis and telomeropathies (PMID: 17392301, 30523342, 34019641). ClinVar contains an entry for this variant (Variation ID: 39122). 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 not expected to disrupt TERT protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects TERT function (PMID: 17392301). 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.
Fulgent Genetics, Fulgent Genetics	RCV002482937	SCV002785234	uncertain significance	Interstitial lung disease 2; Aplastic anemia; Dyskeratosis congenita, autosomal dominant 1; Acute myeloid leukemia; Dyskeratosis congenita, autosomal dominant 2; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1; Melanoma, cutaneous malignant, susceptibility to, 9	2021-08-04	criteria provided, single submitter	clinical testing
GeneDx	RCV003329237	SCV004036830	uncertain significance	not provided	2023-09-19	criteria provided, single submitter	clinical testing	Observed in individuals with shortened telomeres and personal history of idiopathic pulmonary fibrosis or thrombocytopenia in published literature (Armanios et al., 2007; Gutierrez-Rodrigues et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23716176, 21520174, 20301779, 17392301, 28373299, 17825470, 23618685, 31426295, 30523342, 34019641)
Baylor Genetics	RCV003460538	SCV004205829	uncertain significance	Dyskeratosis congenita, autosomal dominant 2	2024-03-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003329237	SCV005877736	uncertain significance	not provided	2024-11-12	criteria provided, single submitter	clinical testing	The TERT c.3329C>T; p.Thr1110Met variant (rs199422306, ClinVar Variation ID: 39122) is reported in the literature in individuals affected with idiopathic pulmonary fibrosis or thrombocytopenia and these individuals also had shortened telomeres compared to controls (Armanios 2007, Gutierrez-Rodrigues 2019). Additionally, this variant was found in a patient with myelodysplastic syndrome however the variant was not confirmed to be germline (Reilly 2021). This variant is found in the general population with an overall allele frequency of 0.003% (9/274,156 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.509). In vitro functional analyses demonstrate decreased telomere elongation activity compared to wildtype (Armanios 2007, Reilly 2021). However, given the lilmited clinical and functional data, the significance of this variant is uncertain at this time. References: Armanios MY et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007 Mar 29;356(13):1317-26. PMID: 17392301. Gutierrez-Rodrigues F et al. Pathogenic TERT promoter variants in telomere diseases. Genet Med. 2019 Jul;21(7):1594-1602. PMID: 30523342. Reilly CR et al. The clinical and functional effects of TERT variants in myelodysplastic syndrome. Blood. 2021 Sep 9;138(10):898-911. PMID: 34019641.
Ambry Genetics	RCV005278530	SCV005948436	uncertain significance	Dyskeratosis congenita	2024-12-14	criteria provided, single submitter	clinical testing	The p.T1110M variant (also known as c.3329C>T), located in coding exon 16 of the TERT gene, results from a C to T substitution at nucleotide position 3329. The threonine at codon 1110 is replaced by methionine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
GeneReviews	RCV000032395	SCV000056051	not provided	Interstitial lung disease 2		no assertion provided	literature only
Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center	RCV002509177	SCV002547380	likely risk allele	Pulmonary fibrosis	2022-06-09	no assertion criteria provided	research	Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted