ClinVar Miner

Submissions for variant NM_198253.2(TERT):c.604G>A (p.Ala202Thr) (rs121918661)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000459343 SCV000551526 uncertain significance Idiopathic fibrosing alveolitis, chronic form; Dyskeratosis congenita, autosomal dominant, 2 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 202 of the TERT protein (p.Ala202Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs121918661, ExAC 0.2%). This variant has been reported in individuals affected with aplastic anemia (PMID: 15814878, 20858879), as well as in healthy individuals (PMID: 22424236, 15885610). This variant segregated with short telomere length in one family (PMID: 15814878), but did not segregate with aplastic anemia in another family (PMID: 15885610). ClinVar contains an entry for this variant (Variation ID: 12729). Experimental studies have shown that this missense change results in <1% of wild-type telomerase activity in one assay, but 80-90% of wild-type telomerase activity in another assay (PMID: 15814878, 23901009). The clinical significance of these conflicting results is unknown. 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.
GeneDx RCV000489117 SCV000577668 uncertain significance not provided 2018-05-30 criteria provided, single submitter clinical testing In one study, telomerase activity measured by telomeric-repeat amplification analysis demonstrated a 50% reduction of activity in comparison to healthy controls (Yamaguchi et al., 2005). Furthermore, expression of A202T-containing vector in cells lacking telomerase activity showed less than 1% telomerase activity compared to cells transfected with wildtype (Yamaguchi et al., 2005). However, another in vitro functional study demonstrated that a vector containing the A202T variant had activity and processing levels almost comparable to wildtype (Zaug et al., 2013). The A202T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The A202T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Genetic Services Laboratory, University of Chicago RCV000013566 SCV000597471 likely pathogenic Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1 2016-03-14 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000604322 SCV000711360 uncertain significance not specified 2017-04-14 criteria provided, single submitter clinical testing The p.Ala202Thr (NM_198253.2 c.604G>A) variant in TERT has been reported in hete rozygosity in 2 individuals with clinical features of Dyskeratosis congenita an d related disorders (Yamaguchi 2005; ClinVar Variation ID#12729). It was also id entified in another family and did not segregate with disease ( Vulliamy 2005). This variant has been identified in 0.205% (13/6,346) of Latino chromosomes by t he Exome Aggregation Consortium (ExAC,; dbSNP rs1 21918661). In vitro functional studies reportedly suggest that the p.Ala202Thr v ariant may impact protein function (Zaug 2013 and Yamaguchi 2005); however, thes e types of assays may not accurately represent biological function. The amino ac id position is not conserved in mammals and most computational predictions progr ams do not suggest an impact. In summary, the clinical significance of the p.Ala 202Thr variant is uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000489117 SCV000857418 uncertain significance not provided 2017-10-10 criteria provided, single submitter clinical testing
Johns Hopkins Genomics,Johns Hopkins University RCV000758251 SCV000886891 likely benign Dyskeratosis congenita, autosomal dominant, 2 2019-02-26 criteria provided, single submitter clinical testing
OMIM RCV000013566 SCV000033813 pathogenic Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1 2005-04-07 no assertion criteria provided literature only
GeneReviews RCV000032398 SCV000056054 pathologic Aplastic anemia 2012-05-10 no assertion criteria provided curation Converted during submission to Pathogenic.

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