Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000498135 | SCV000589369 | uncertain significance | not provided | 2016-07-20 | criteria provided, single submitter | clinical testing | The V664M variant in the TERT gene has been reported previously in the heterozygous state in an individual with elevated creatine kinase, recurrent infection with hypogammaglobulinemia, dyskeratosis congenita, and mild transaminase abnormalities (Vanderver et al., 2016). This reported variant was found to be maternally inherited. The reported individual also harbored a de novo variant in the TERT gene, and the phase of the de novo variant and the V664M was unknown. The authors noted that telomere length analysis supported a diagnosis of a TERT-related disorder but the data was not shown (Vanderver et al., 2016). The V664M variant is a conservative substitution of one non-polar amino acid for another at a residue that is not conserved across species. In silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. The V664M variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret V664M as a variant of uncertain significance. |
| Invitae | RCV003766790 | SCV004568914 | uncertain significance | Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis | 2023-03-23 | 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: 431836). This missense change has been observed in individual(s) with clinical features of Hoyeraal Hreidarsson syndrome (PMID: 27159321, 33718801). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 664 of the TERT protein (p.Val664Met). |