ClinVar Miner

Submissions for variant NM_198253.3(TERT):c.2080G>A (p.Val694Met)

gnomAD frequency: 0.00001  dbSNP: rs121918662
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002513015 SCV001387911 likely pathogenic Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis 2023-09-08 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 694 of the TERT protein (p.Val694Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of TERT-related conditions (PMID: 15814878, 18635888; Invitae). ClinVar contains an entry for this variant (Variation ID: 12731). 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. Experimental studies have shown that this missense change affects TERT function (PMID: 15814878, 23901009). 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 RCV002415411 SCV002727778 likely pathogenic Dyskeratosis congenita; Hereditary cancer-predisposing syndrome 2016-05-04 criteria provided, single submitter clinical testing The p.V694M variant (also known as c.2080G>A), located in coding exon 5 of the TERT gene, results from a G to A substitution at nucleotide position 2080. The valine at codon 694 is replaced by methionine, an amino acid with highly similar properties. This alteration was first identified in a 34-year old male with moderate aplastic anemia, a family history of myelodysplastic syndrome, and markedly shortened telomeres in peripheral-blood leukocytes (Yamaguchi H et al. N. Engl. J. Med. 2005; 352:1413-24). This alteration has also been observed in an individual with idiopathic pulmonary fibrosis (Cronkhite JT et al. Am. J. Respir. Crit. Care Med. 2008; 178:729-37). Functional studies have found this variant to cause a reduction in telomerase activity when compared to wild type; however, processivity was not affected or increased when compared to wild type (Xie M et al. Nucleic Acids Res. 2010; 38:1982-96, 5:e10680, Zaug AJ et al. Nucleic Acids Res. 2013; 41:8969-78). This variant was previously reported in the SNPDatabase as rs121918662. This amino acid position is 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.
Preventiongenetics, part of Exact Sciences RCV003415694 SCV004114928 uncertain significance TERT-related condition 2022-12-28 criteria provided, single submitter clinical testing The TERT c.2080G>A variant is predicted to result in the amino acid substitution p.Val694Met. This variant was reported in an individual with aplastic anemia and shortened telomeres and a family history of myelodysplastic syndrome (Yamaguchi et al. 2005. PubMed ID: 15814878). This variant has also been reported in an individual with a personal and family history of pulmonary fibrosis (Cronkhite et al. 2008. PubMed ID: 18635888). Functional studies found this variant resulted in decreased telomerase activity; however, studies disagreed as to the extent of the decrease ranging from <1% to ~40% compared to wild type (Yamaguchi et al. 2005. PubMed ID: 15814878; Zaug et al. 2013. PubMed ID: 23901009). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GeneDx RCV003441715 SCV004169041 likely pathogenic not provided 2023-11-12 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16990594, 25906514, 20502709, 23618685, 23538340, 16207588, 17825470, 20044353, 23901009, 25244922, 19636400, 19760749, 15814878, 18635888, 23716176, 20301779, 34019641, 31943309, 36496180)
OMIM RCV000013568 SCV000033815 pathogenic Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 2005-04-07 no assertion criteria provided literature only
GeneReviews RCV000032373 SCV000056029 not provided Aplastic anemia no assertion provided literature only
Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center RCV002509152 SCV002547406 likely risk allele Pulmonary fibrosis 2022-06-09 no assertion criteria provided research Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted

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