Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Bertuch Lab, |
RCV001267811 | SCV001396722 | pathogenic | Diamond-Blackfan anemia | criteria provided, single submitter | clinical testing | We have identified a novel, de novo variant in RPS20 in a patient with Diamond-Blackfan anemia. RPS20 is a component of the ribosome, which is central in the pathogenesis of DBA. The mutated residue, p.I84, is located within a highly evolutionarily conserved motif [R(I/V/T)HKR] and within a positively charged pocket. The pI84N mutation destabilizes the RPS20 protein, as levels of transiently overexpressed mutant RPS20 were markedly reduced relative to the wild type control, and RPS20 protein from the proband was similarly reduced relative to that of his father or sibling. Lymphoblastoid cells bearing the RPS20 p.I84N variant exhibited a ribosome and polysome profile and increased 28S/18S rRNA ratio consistent with a defect in the 40S ribosome subunit. Yeast bearing mutations of the cognate residue showed growth, ribosome biogenesis, and polysome defects, indicating an impairment of translation. In silico analyses from numerous predictions tools were consistent with the mutation being damaging and disease causing. A second patient with DBA was found to have a different missense mutation at the same RPS20 residue. In summary, this variant has strong evidence for being pathogenic according to ACMG 2015 guidelines and functional data and allelic data. |