Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000442656 | SCV000517078 | pathogenic | not provided | 2015-05-08 | criteria provided, single submitter | clinical testing | The R378Q variant in the DKC1 gene has been reported previously in a patient with Hoyeraal-Hreidarrson (HH) syndrome, who had microcephaly, enteropathy, and immunodeficiency (Vulliamy et al.,2011). The R378Q 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 R378Q variant is a semi-conservative amino acid substitution, which occurs at aposition that is conserved across species. In silico analysis predicts this variant is probably damaging tothe protein structure/function. Missense variants in nearby residues (P384L and A386T) have beenreported in the Human Gene Mutation Database in association with DKC1-related disorders (Stenson etal., 2014), supporting the functional importance of this region of the protein. We interpret R378Q as a pathogenic variant. |
DASA | RCV000779660 | SCV002073752 | likely pathogenic | Dyskeratosis congenita, X-linked | 2022-02-05 | criteria provided, single submitter | clinical testing | The c.1133G>A;p.(Arg378Gln) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 379736; PMID: 31474318; 21931702) - PS4_moderate. This variant is not present in population databases (rs1057520719; gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Missense variant in DKC1 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic. |
Invitae | RCV003530047 | SCV004299726 | uncertain significance | Dyskeratosis congenita | 2023-03-07 | criteria provided, single submitter | clinical testing | 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 DKC1 protein function. ClinVar contains an entry for this variant (Variation ID: 379736). This missense change has been observed in individuals with cerebellar hypoplasia (CBLH) and/or Hoyeraal-Hreidarsson syndrome (PMID: 21931702, 28930861, 31474318). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 378 of the DKC1 protein (p.Arg378Gln). 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. |
Dobyns Lab, |
RCV000779660 | SCV000916341 | pathogenic | Dyskeratosis congenita, X-linked | 2019-02-18 | no assertion criteria provided | research | |
University of Washington Center for Mendelian Genomics, |
RCV001257984 | SCV001434797 | likely pathogenic | Congenital cerebellar hypoplasia | no assertion criteria provided | research |