Submission Details

The RPS19 gene is located on chromosome 19 at 19q13.2 and encodes ribosomal protein S19, a component of the 40S subunit, which is required for pre-rRNA processing and maturation of 40S ribosomal subunits. RPS19 was first reported in relation to autosomal recessive Diamond-Blackfan anemia (DBA or Diamond Blackfan Anemia 1) in 1999 (Draptchinskaia et al., 1999, PMID: 9988267; Ramenghi et al., 1999, PMID: 10192448; Willig et al., 1999, PMID: 10590074). DBA is a rare, congenital bone-marrow-failure syndrome associated with red blood cell aplasia, macrocytic anemia , poor growth, increased risk of malignancy. Other features may include congenital malformations involving the craniofacial, upper limb, heart, and urinary systems. Significant clinical heterogeneity is seen. At least 10 variants (missense and nonsense) that have been reported in 11 probands in 4 publications (PMID: 9988267; Schuster et al., 2010, PMID: 20395159; Da Costa et al., 2003, PMID: 12586610; PMID: 10590074) are included in this curation. The maximum score for genetic evidence, 12 pts., has been reached. The mechanism of pathogenicity is reported to be haploinsufficiency. This gene-disease relationship is also supported by experimental evidence including a mouse model, expression data, and protein interaction evidence (Gregory et al., 2007, PMID: 17726054; McGowan et al., 2008, PMID: 18641651). The gene is normally expressed in relevant tissues that are associated with the disease phenotypes. RPS19 was shown to co-precipitate with both 18S rRNA and 25S rRNA and to be a component of the 40S ribosomal subunit. In summary, there is definitive evidence to support the relationship between RPS19 and autosomal recessive Diamond Blackfan syndrome (Diamond Blackfan anemia 1). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 03.01.2023 (SOP Version 9).