Submissions for variant NM_198253.3(TERT):c.2812C>T (p.Arg938Trp)

gnomAD frequency: 0.00001  dbSNP: rs1422814635

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Godley laboratory, The University of Chicago	RCV001172444	SCV001252700	likely pathogenic	Macrocytic anemia; Premature graying of hair; Abnormal pulmonary interstitial morphology; Short telomere length	2020-05-18	criteria provided, single submitter	clinical testing	This heterozygous variant was found in germline in a patient with ILD/UIP diagnosed at age 48. The telomere length was below the 1st percentile in lymphocytes. The patient also displayed other phenotypic features such as early greying and macrocytic anemia. The following ACMG/AMP criteria were used: PS4_moderate, PM2, PP2, PP3.
Genetic Services Laboratory, University of Chicago	RCV001819875	SCV002065716	likely pathogenic	not provided	2021-04-28	criteria provided, single submitter	clinical testing	DNA sequence analysis of the TERT gene demonstrated a sequence change, c.2812C>T, in exon 11 that results in an amino acid change, p.Arg938Trp. This sequence change is absent in the gnomAD population database. This sequence change has been identified in a patient with idiopathic pulmonary fibrosis (PMID: 28099038).The p.Arg938Trp change affects a poorly conserved amino acid residue located in the CTE domain of the TERT protein. The p.Arg938Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, CADD, REVEL). Further analysis of peripheral blood lymphocytes in this patient showed short telomere length below the first percentile (PMID: 33035329). Collectively, these evidences suggest p.Arg938Trp is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002559651	SCV002255526	likely pathogenic	Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis	2023-09-08	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with idiopathic pulmonary fibrosis (PMID: 28099038; Invitae). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 938 of the TERT protein (p.Arg938Trp). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 916674). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TERT protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV004559909	SCV002747635	likely pathogenic	Dyskeratosis congenita	2022-04-27	criteria provided, single submitter	clinical testing	The n.2812C>T variant (also known as c.2812C>T p.R938W), located in exon 11 of the TERT gene, results from a C to T substitution at nucleotide position 2812. The arginine at codon 938 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in an individual with pulmonary disease, macrocytic anemia, early graying, and short telomere length (Feurstein S et al. Blood Adv, 2020 10;4:4873-4886). The alteration was also reported in an individual with idiopathic pulmonary fibrosis (Petrovski S et al. Am J Respir Crit Care Med, 2017 07;196:82-93). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center	RCV002509621	SCV002547387	likely risk allele	Pulmonary fibrosis	2022-06-09	no assertion criteria provided	research	Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted