ClinVar Miner

Submissions for variant NM_198253.3(TERT):c.2431C>T (p.Arg811Cys)

gnomAD frequency: 0.00001  dbSNP: rs199422301
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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 RCV002513176 SCV001205214 uncertain significance Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis 2023-07-10 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 811 of the TERT protein (p.Arg811Cys). This variant is present in population databases (rs199422301, gnomAD 0.0008%). This missense change has been observed in individual(s) with dyskeratosis congenita in the homozygous state and/or familial pulmonary fibrosis in the heterozygous state (PMID: 17785587, 28192371). ClinVar contains an entry for this variant (Variation ID: 29900). 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: 17785587, 26887940). 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 RCV001797047 SCV002038816 likely pathogenic not provided 2021-08-11 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect as this variant was defective in binding to telomeres, resulting in uncapping and higher apoptosis, and showing a 50% reduction in telomerase activity in transfected cells (Chu et al., 2016; Marrone et al., 2007).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17785587, 26887940, 23538340, 23716176, 29691679, 26581521, 20301779, 28192371)
3billion RCV002051796 SCV002318673 uncertain significance Dyskeratosis congenita, autosomal dominant 2 2022-03-22 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004). A missense variant is a common mechanism. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
OMIM RCV000022784 SCV000044073 pathogenic Autosomal recessive dyskeratosis congenita 4 2007-12-15 no assertion criteria provided literature only
GeneReviews RCV000032383 SCV000056039 not provided Dyskeratosis congenita, autosomal recessive 1 no assertion provided literature only

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