Submission Details

The RPL5 gene is located on chromosome 1 at 1p22.1 and encodes ribosomal protein L5, which is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. RPL5 was first reported in relation to autosomal dominant Diamond-Blackfan anemia 6 in 2008 (Gazda et al., PMID:19061985). Diamond-Blackfan anemia 6 is a rare, congenital bone-marrow-failure syndrome, characterized by red blood cell aplasia, macrocytic anemia, poor growth, increased risk of malignancy. Other features include congenital malformations involving the craniofacial, upper limb, heart, and urinary systems. Significant clinical heterogeneity is seen. At least 11 unique variants (missense, nonsense, frameshift, splice site) that have been reported in 11 probands in 6 publications (PMID: 19061985; Cmejla et al., 2009, PMID: 19191325; Gerrad et al., 2013, PMID: 23718193; Errichiello et al., 2017, PMID: 28376382; Farah et al., 2020, PMID: 30933022; Chhabra et al., 2021, PMID: 33197791) are included in this curation. More evidence is available in the literature, but 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 two mouse models, biochemical function data, expression data, and evidence of functional alteration (Kazerounian et al., 2019, PMID: 32309614; Yu et al., 2021, PMID: 34464976; PMID: 19061985, Fukui et al., 2021; PMID: 34587661). In summary, RPL5 is definitively associated with autosomal dominant Diamond-Blackfan anemia 6. 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).