RIPOR2 was first reported in relation to autosomal recessive nonsyndromic genetic deafness in 2014 (Diaz-Horta et al.; PMID: 24958875). 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 dominant nonsyndromic genetic deafness has been curated separately. Two variants (splice-site, nonsense) that have been reported in nine probands in two publications (PMIDs: 24958875, 37864412) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse model, zebrafish model, expression-level evidence, functional alteration evidence; PMIDs: 24958875, 27269051, 30280293). Mutant mice and zebrafish show significant hearing loss. Expression-level evidence indicates that the gene is expressed in inner and outer hair cells. The gene is shown to interact with MYH9, which is classified as definitive for an autosomal dominant condition, of which hearing loss is a feature. This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 9/18/2018. It was re-evaluated on 5/15/2024. As a result of this reevaluation, the classification changed from moderate to strong, due to the addition of genetic evidence and experimental evidence (protein interaction evidence) (PMIDs: 30280293, 37864412). In summary, there is strong evidence to support the relationship between RIPOR2 and autosomal recessive nonsyndromic hearing loss. More than two publications of genetic evidence are required for a definitive classification, and there are currently only two. We will re-evaluate this gene-disease relationship in the future to determine if an upgraded classification of definitive is warranted. This classification was approved by the ClinGen Hearing Loss GCEP on the meeting date 5/15/2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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