ClinVar Miner

Submissions for variant NM_198253.3(TERT):c.2051A>G (p.Asp684Gly) (rs776981958)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Degerman lab,Umeå University RCV000677345 SCV000611697 likely pathogenic Dyskeratosis congenita, autosomal dominant, 2; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1 2017-11-23 criteria provided, single submitter clinical testing
Invitae RCV000799933 SCV000939622 uncertain significance Idiopathic Pulmonary Fibrosis; Dyskeratosis congenita, autosomal dominant, 2 2019-08-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 684 of the TERT protein (p.Asp684Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs776981958, ExAC 0.8%). This variant has been observed as homozygous in two siblings with short telomeres, one of them affected with myelodysplastic syndrome (MDS), dystrophic nails and reticular skin pigmentation, and the other with tongue cancer. It has also been observed in heterozygosis in an individual with MDS, lung fibrosis, liver cirrhosis, and short telomeres and in an individual with thrombocytopenia, dysmorphic nails and rough tongue (PMID: 29483670). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Mayo Clinic Laboratories, Mayo Clinic RCV001508165 SCV001714132 uncertain significance not provided 2019-12-19 criteria provided, single submitter clinical testing

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