Submissions for variant NM_198253.3(TERT):c.2768C>T (p.Pro923Leu)

dbSNP: rs387907251

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513273	SCV001205864	uncertain significance	Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis	2023-03-07	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 36950). This missense change has been observed in individual(s) with diffuse pulmonary fibrosis. However, it is uncertain if the variant is of germline or somatic origin (PMID: 22512499). This variant is present in population databases (rs387907251, gnomAD 0.007%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 923 of the TERT protein (p.Pro923Leu).
GeneDx	RCV001753435	SCV002005438	uncertain significance	not provided	2023-11-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in patients with a personal and/or family history of a TERT-related disorder and shortened telomeres (PMID: 23618685, 29976374); This variant is associated with the following publications: (PMID: 26642856, 23618685, 22512499, 29976374, 33203829, 31256854, 25393420)
Genetic Services Laboratory, University of Chicago	RCV001753435	SCV002067437	likely pathogenic	not provided	2020-02-24	criteria provided, single submitter	clinical testing	This sequence change has been reported in the gnomAD database in one individual (dbSNP rs387907251). This sequence change has been identified in an individual with telomere-related pulmonary fibrosis and bone marrow failure. This patient was reported to have a family history consistent with TERT-related disorders, including pulmonary fibrosis, thrombocytopenia, and acute myeloid leukemia; however, affected relatives were not analyzed for this sequence change (PMID: 22512499). The p.Pro923Leu change affects a highly conserved amino acid residue located in a domain of the TERT protein that is known to be functional. The p.Pro923Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).
Ambry Genetics	RCV004558275	SCV002752282	likely pathogenic	Dyskeratosis congenita	2022-04-14	criteria provided, single submitter	clinical testing	The p.P923L variant (also known as c.2768C>T), located in coding exon 11 of the TERT gene, results from a C to T substitution at nucleotide position 2768. The proline at codon 923 is replaced by leucine, an amino acid with similar properties. This variant was first described in an individual with idiopathic pulmonary fibrosis, mild pancytopenia, and short telomere lengths. This individual's family history was remarkable for a parent and 3 siblings with pulmonary fibrosis; two siblings also had thrombocytopenia and acute myeloid leukemia, respectively (Gansner JM et al. N. Engl. J. Med., 2012 Apr;366:1551-3). In addition, this variant was described in a second individual with idiopathic pulmonary fibrosis and hypocellularity on bone marrow biopsy who was listed for lung transplantation (George G et al. Chest, 2015 Jun;147:1549-1557). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767022	SCV005381182	uncertain significance	not specified	2024-08-13	criteria provided, single submitter	clinical testing	Variant summary: TERT c.2768C>T (p.Pro923Leu) results in a non-conservative amino acid change located in the Reverse transcriptase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249260 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2768C>T has been reported in the literature in individuals affected with TERT-Related Disorders (Gansner_2012, Stark_2022, Ferrer_2023). These report(s) do not provide unequivocal conclusions about association of the variant with TERT-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37665761, 22512499, 35083318). ClinVar contains an entry for this variant (Variation ID: 36950). Based on the evidence outlined above, the variant was classified as uncertain significance.
OMIM	RCV000030631	SCV000053309	pathogenic	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1	2012-04-19	no assertion criteria provided	literature only