Submissions for variant NM_198253.3(TERT):c.2377G>A (p.Glu793Lys)

dbSNP: rs1043358053

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002548597	SCV001564266	uncertain significance	Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis	2022-06-10	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 793 of the TERT protein (p.Glu793Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TERT-related conditions. ClinVar contains an entry for this variant (Variation ID: 1058722). 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. 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.
GeneDx	RCV002245979	SCV002512835	uncertain significance	not provided	2022-04-21	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; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV004557570	SCV002737004	uncertain significance	Dyskeratosis congenita	2014-11-06	criteria provided, single submitter	clinical testing	The p.E793K variant (also known as c.2377G>A), located in coding exon 7 of the TERT gene, results from a G to A substitution at nucleotide position 2377. The glutamic acid at codon 793 is replaced by lysine, an amino acid with some similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6245 samples (12490 alleles) with coverage at this position. This amino acid position is well conserved on limited sequence alignment. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004531172	SCV004119126	uncertain significance	TERT-related disorder	2023-07-11	criteria provided, single submitter	clinical testing	The TERT c.2377G>A variant is predicted to result in the amino acid substitution p.Glu793Lys. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been interpreted as uncertain in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/1058722/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center	RCV002509674	SCV002547401	likely risk allele	Pulmonary fibrosis	2022-06-09	no assertion criteria provided	research	Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted