Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002406005 | SCV002714490 | likely pathogenic | Diamond-Blackfan anemia | 2018-03-06 | criteria provided, single submitter | clinical testing | The p.R56Q variant (also known as c.167G>A), located in coding exon 2 of the RPS19 gene, results from a G to A substitution at nucleotide position 167. The arginine at codon 56 is replaced by glutamine, an amino acid with highly similar properties. This variant has been identified in multiple individuals with Diamond-Blackfan anemia (Willig TN et al. Blood, 1999 Dec;94:4294-306; Gazda HT et al. Br. J. Haematol., 2004 Oct;127:105-13; Campagnoli MF et al. Hum. Mutat., 2008 Jul;29:911-20; Pospisilova D et al. Blood Cells Mol. Dis., 2012 Apr;48:209-18). In HEK293 cells, RPS19 protein with this variant showed nucleolar localization similar to wild type; however, the mutant protein was not associated with the ribosomes (Angelini M et al. Hum. Mol. Genet., 2007 Jul;16:1720-7). Functional analyses in K562 cells expressing this variant demonstrated reduced RPS19 protein levels and a lower level of basal translation compared to wild type (Cmejlova J et al. Haematologica, 2006 Nov;91:1456-64; Kuramitsu M et al. Br. J. Haematol., 2008 Feb;140:348-59). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Prevention |
RCV004725271 | SCV005336839 | likely pathogenic | RPS19-related disorder | 2024-09-03 | no assertion criteria provided | clinical testing | The RPS19 c.167G>A variant is predicted to result in the amino acid substitution p.Arg56Gln. This variant has been reported in multiple individuals with Diamond-Blackfan anemia (DBA) (Willig et al. 1999. PubMed ID: 10590074; Gazda et al. 2004. PubMed ID: 15384984). In vitro functional studies have demonstrated that RPS19 protein with the p.Arg56Gln variant localizes properly to the nucleolus but is not incorporated into ribosomes, leading to reduced protein translation levels relative to wild type (Cmejlova et al. 2006. PubMed ID: 17082006; Angelini et al. 2007. PubMed ID: 17517689). This variant has not been reported in the gnomAD database, indicating this variant is rare. Other missense variants at the same amino acid residue (p.Arg56Pro, p.Arg56Leu) have also been reported in individuals with DBA (Ozono et al. 2016. PubMed ID: 27601194; Table S4A, Mirabello et al. 2017. PubMed ID: 28280134). Taken together, the p.Arg56Gln variant is interpreted as likely pathogenic. |