Submission Details

RIPOR2 was first reported in relation to autosomal dominant nonsyndromic genetic deafness in 2020 (de Brujin et al; PMID: 32631815). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into two disease entities, autosomal recessive nonsyndromic genetic deafness (OMIM:616515) and autosomal dominant nonsyndromic genetic deafness (OMIM:607017). The split curation for autosomal recessive nonsyndromic genetic deafness has been curated separately. One variant (in-frame deletion) that has been reported in over fifty probands from twelve families (with a founder effect demonstrated for at least seven of the families) in one publication (PMIDs: 32631815) is included in this curation. Analysis of this variant in mice shows mislocalization, supporting impaired function of protein. Thus, the mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse model, expression-level evidence, PMID: 24958875). Heterozygous mutant mice show mild hearing loss. Expression-level evidence indicates that the gene is expressed in inner and outer hair cells. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Hearing Loss GCEP on the meeting date 5/15/2024 (SOP Version 10).