Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002518376 | SCV000291862 | likely benign | Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis | 2024-01-04 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV001549913 | SCV001770150 | uncertain significance | not provided | 2020-11-25 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate no damaging effect: TERT protein activity similar to wild type when studied independently (Alder 2011); Observed in individuals with aplastic anemia (Ghemlas 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function This variant is associated with the following publications: (PMID: 31871297, 26136524, 23538340, 24798238, 21483807, 26851889, 22900168) |
| St. |
RCV003325196 | SCV004031165 | uncertain significance | Dyskeratosis congenita, autosomal dominant 2 | 2023-08-30 | criteria provided, single submitter | clinical testing | The TERT c.2371G>A (p.Val791Ile) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function and functional studies suggest that this variant alone does not affect TERT function (PMID: 21483807). This variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PMID: 27535533). This variant has been reported in an individual with aplastic anemia (PMID: 26136524). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. |
| Baylor Genetics | RCV003325196 | SCV004208123 | uncertain significance | Dyskeratosis congenita, autosomal dominant 2 | 2024-03-29 | criteria provided, single submitter | clinical testing | |
| Center for Genomic Medicine, |
RCV003992244 | SCV004809952 | uncertain significance | Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 | 2024-04-04 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV004734891 | SCV005351628 | uncertain significance | TERT-related disorder | 2024-09-25 | no assertion criteria provided | clinical testing | The TERT c.2371G>A variant is predicted to result in the amino acid substitution p.Val791Ile. This variant has been reported along with a second TERT variant (p.Val867Met) in a family with familial pulmonary fibrosis (Alder et al. 2011. PubMed ID: 21483807). These two variants were found on the same allele (in cis) and segregated with the disease across four generations in this family. In vitro functional studies indicate that these two variants together cause defects in repeat addition processivity. However, the p.Val791Ile alone did not have obvious defects in activity or processivity (Alder et al. 2011. PubMed ID: 21483807). This variant has also been reported in the heterozygous state in an individual with dyskeratosis congenita with severe aplastic anemia, but no additional studies were performed (Supplemental Table 4, Ghemlas et al. 2015. PubMed ID: 26136524) and was identified in an individual with pancreatic cancer and a family history of endometrial, osteosarcoma, and thyroid cancer (Goldstein et al. 2019. PubMed ID: 31871297). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/242228/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |