Submissions for variant NM_001022.4(RPS19):c.185G>A (p.Arg62Gln)

dbSNP: rs1555841301

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000538681	SCV000637224	pathogenic	Diamond-Blackfan anemia	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 62 of the RPS19 protein (p.Arg62Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Diamond-Blackfan anaemia (DBA) (PMID: 10753603, 12750732, 15384984, 18412286, 20378560). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 463372). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects RPS19 function (PMID: 16159874, 17053056, 17082006, 17517689, 17726054, 24952648). This variant disrupts the p.Arg62 amino acid residue in RPS19. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15384984, 17517689, 18412286, 20606162). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000538681	SCV002719603	pathogenic	Diamond-Blackfan anemia	2023-02-09	criteria provided, single submitter	clinical testing	The p.R62Q pathogenic mutation (also known as c.185G>A), located in coding exon 3 of the RPS19 gene, results from a G to A substitution at nucleotide position 185. The arginine at codon 62 is replaced by glutamine, an amino acid with highly similar properties. This mutation was first described in a 2-month-old infant with Diamond-Blackfan anemia (DBA) (Cmejla R, et al. Blood Cells Mol. Dis. 2000 Apr; 26(2):124-32). Subsequent studies have identified this mutation in additional infants and probands with DBA, and segregation with disease in families has been reported (Proust A et al. Hematol J. 2003; 4(2):132-6; Konno Y et al. Haematologica. 2010 Aug; 95(8):1293-9; Ichimura T et al. Int J Hematol. 2017 Apr;105(4):515-520; Muramatsu H. Genet. Med. 2017 07;19(7):796-802; Cole S et al. Front Genet, 2022 Jul;13:914141). This mutation has been reported to disrupt protein stability and prevent protein assembly into a mature ribosome in functional assays (Angelini M, et al. Hum. Mol. Genet. 2007 Jul; 16(14):1720-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702674	SCV001930469	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001702674	SCV001956686	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003900162	SCV004716884	pathogenic	RPS19-related disorder	2023-11-17	no assertion criteria provided	clinical testing	The RPS19 c.185G>A variant is predicted to result in the amino acid substitution p.Arg62Gln. This variant has been reported in the heterozygous state in multiple unrelated individuals and families with Diamond-Blackfan anemia (DBA) (see for example, Cmejla R et al. 2000. PubMed ID: 10753603; Gazda HT et al. 2004. PubMed ID: 15384984; Konno Y et al. 2010. PubMed ID: 20378560; Ichimura T et al. 2016. PubMed ID: 27882484). In one large family, this variant segregated with DBA in 9 of 10 carriers (Cole S et al. 2022. PubMed ID: 35923690). In vitro functional studies show this variant significantly inhibits the rate of protein synthesis compared to control, is degraded more rapidly compared to control, and results in altered pre-rRNA processing leading to impaired ribosome biogenesis (Cmejlova J et al 2006. PubMed ID: 17082006; Angelini M et al 2007. PubMed ID: 17517689; Choesmel V et al. 2007 PubMed ID: 17053056). Another missense change impacting the same amino acid (p.Arg62Trp) has been reported in individuals with DBA and has also been shown to negatively impact RPS19 protein function, suggesting that the Arg62 residue is critical to protein function (Gazda HT et al 2004. PubMed ID: 15384984; Devlin et al. 2010. PubMed ID: 20606162). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Taken together, the c.185G>A (p.Arg62Gln) variant is interpreted as pathogenic.