ClinVar Miner

Submissions for variant NM_001363.5(DKC1):c.1223C>T (p.Thr408Ile) (rs199422254)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255428 SCV000321554 pathogenic not provided 2015-05-28 criteria provided, single submitter clinical testing The T408I missense variant in the DKC1 gene has been reported previously in association with X-linked DC (Vulliamy et al., 2006). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. T408I 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. This substitution occurs at a position that is conserved across species and in-silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, missense variants in nearby residues (G402R/E, T405A, P409R/L) have been reported in the Human Gene Mutation Database in association with DKC1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein.
Invitae RCV001048156 SCV001212146 uncertain significance Dyskeratosis congenita 2019-12-02 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 408 of the DKC1 protein (p.Thr408Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with dyskeratosis congenita (PMID: 16332973, Invitae). ClinVar contains an entry for this variant (Variation ID: 38941). 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 disruptive, 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.
GeneReviews RCV000032192 SCV000055782 pathologic Dyskeratosis congenita, X-linked 2012-05-10 no assertion criteria provided curation Converted during submission to Pathogenic.

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