ClinVar Miner

Submissions for variant NM_198253.2(TERT):c.3150G>C (p.Lys1050Asn) (rs373400596)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000344253 SCV000452230 uncertain significance Dyskeratosis congenita, autosomal dominant, 2 2016-08-02 criteria provided, single submitter clinical testing The TERT c.3150G>C (p.Lys1050Asn) missense variant has been identified by Collopy et al. (2015) in a homozygous state in one individual and his sister, both of whom have bone marrow failure and nail dystrophy. Both individuals also showed a shortened telomere length. The variant was shown to result in 56% of telomerase activity compared to wild type. The brother was also found to carry a heterozygous variant in the TERC gene which resulted in 4.7% telomerase activity. Control data are unavailable for the p.Lys1050Asn variant, which is reported at a frequency of 0.00047 in the European American population of the Exome Sequencing Project. The evidence for this variant is limited. The p.Lys1050Asn variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for dyskeratosis congenita. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Clinical Services Laboratory,Illumina RCV000398654 SCV000452231 uncertain significance Aplastic anemia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000309581 SCV000452232 benign Idiopathic fibrosing alveolitis, chronic form 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000457571 SCV000551540 uncertain significance Idiopathic fibrosing alveolitis, chronic form; Dyskeratosis congenita, autosomal dominant, 2 2018-12-16 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 1050 of the TERT protein (p.Lys1050Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs373400596, ExAC 0.02%). This variant has been reported in a single family affected with dyskeratosis congenita. However, all first degree relatives did not have molecular testing and a TERC variant was also present in the family. Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 26024875). ClinVar contains an entry for this variant (Variation ID: 350518). This variant was shown to have a 44% reduction in wild-type telomerase activity. However, normal telomerase cutoffs have not been well established for this assay (PMID: 26024875). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 RCV000501666 SCV000597462 likely pathogenic Dyskeratosis congenita 2016-03-10 criteria provided, single submitter clinical testing

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