RNU5B-1

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:1060179

Submitter: ClinGen

*RNU5B-1* is located in chromosome 15 at 15q22.31 and encodes the U5B small nuclear 1 RNA, a key component of the major spliceosome composed of five snRNAs (U1, U2, U4, U5, and U6). The U5 snRNA is involved in forming the U4/U6 x U5 tri-snRNP complex, which is a critical intermediate in the assembly of the major spliceosome. This tri-snRNP complex facilitates ​​the correct positioning of the U4, U5, and U6 snRNAs, allowing them to interact with the pre-mRNA and carry out the splicing reaction. *RNU5B-1* was first reported in relation to autosomal dominant *RNU5B-1* related neurodevelopmental disorder with seizures and joint laxity in 2025 (Nava et al. 2025 PMID: 40379786 and Jackson et al. 2025 PMID: 40442284). This disease is characterized by global developmental delay, hypotonia, macrocephaly, and failure to thrive. Evidence supporting this gene-disease relationship includes case-level data and experimental evidence. Five unique pathogenic/likely pathogenic non-coding variants (2 single nucleotides, 2 single base-pair insertion, 1 transversion) have been reported in fifteen probands across 2 publications and are include in this curation ( PMIDs:40379786, 40442284). Pathogenic variants are clustered within a small region, corresponding to the highly conserved U5 5′ loop I, which is depleted in variants in gnomAD v4.1.0 and the UK Biobank (PMIDs:40379786, 40442284). Two patients reported with variants of uncertain significance (n.24G>C, n.74T>C) which are located beyond the constrained region were not counted towards genetic evidence points (PMID: 40379786). This gene-disease relationship is also supported by biochemical, protein interaction, functional alteration and expression evidence. U5 snRNA interacts with other snRNAs and plays a direct role in achieving splicing precision by actively recognizing and binding exons (PMID: 34276781). Splicing analysis in patients with *RNU5B-1* variants demonstrate significant alternative 5′SS and 3′SS events by *RNU5B-1* n.39C>G and *RNU5B-1* n.44A>G compared to controls (PMID: 40379786). Additionally, *RNU5B-1* is expressed in multiple brain regions (PMID: 40379786). In summary, there is strong evidence to support the relationship between *RNU5B-1* and autosomal dominant *RNU5B-1* related neurodevelopmental disorder with seizures and joint laxity. Three years must elapse from the first proposal of the assertion to reach a definitive classification without any valid contradictory evidence. We will re-evaluate this gene-disease relationship at that time to determine if an upgraded classification of definitive is warranted. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date September 19th, 2025 (SOP Version 11).