ClinVar Miner

Submissions for variant NM_001363.5(DKC1):c.259A>G (p.Ile87Val) (rs782202263)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478198 SCV000569543 uncertain significance not provided 2016-03-01 criteria provided, single submitter clinical testing The I87V variant in the DKC1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I87V variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I87V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret I87V as a variant of uncertain significance.
Invitae RCV001210991 SCV001382511 uncertain significance Dyskeratosis congenita 2019-09-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 87 of the DKC1 protein (p.Ile87Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs782202263, ExAC 0.002%). This variant has not been reported in the literature in individuals with DKC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 420625). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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