ClinVar Miner

Submissions for variant NM_198253.3(TERT):c.1304T>A (p.Val435Glu)

dbSNP: rs1561213530
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002531428 SCV000812388 uncertain significance Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis 2024-04-11 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 435 of the TERT protein (p.Val435Glu). 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: 565378). 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 not expected to disrupt TERT protein function with a negative predictive value of 95%. 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.
Genetic Services Laboratory, University of Chicago RCV001816693 SCV002068449 uncertain significance not specified 2018-02-22 criteria provided, single submitter clinical testing
GeneDx RCV002291685 SCV002584225 uncertain significance not provided 2023-06-14 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate in vitro telomerase activity and processivity similar to wildtype (Tomlinson et al., 2021); Identified in an individual with myelodysplastic syndrome, but testing was unable to determine whether the variant was a somatic alteration or present in the patient's germline (Tomlinson et al., 2021); This variant is associated with the following publications: (PMID: 32313107)
Ambry Genetics RCV004559348 SCV002693738 uncertain significance Dyskeratosis congenita 2022-04-12 criteria provided, single submitter clinical testing The p.V435E variant (also known as c.1304T>A), located in coding exon 2 of the TERT gene, results from a T to A substitution at nucleotide position 1304. The valine at codon 435 is replaced by glutamic acid, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002485583 SCV002778621 uncertain significance Interstitial lung disease 2; Aplastic anemia; Dyskeratosis congenita, autosomal dominant 1; Acute myeloid leukemia; Dyskeratosis congenita, autosomal dominant 2; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1; Melanoma, cutaneous malignant, susceptibility to, 9 2022-03-04 criteria provided, single submitter clinical testing

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