CLRN2 was first reported in relation to autosomal recessive nonsyndromic hearing loss in 2021 (Vona et al., PMID: 33496845). Hearing loss in affected probands with variants in this gene is moderate-to-profound. 2 variants (missense, nonsense) that have been reported in 2 probands in 2 publications (PMIDs: 33496845, 39446282) are included in this curation. This variant segregated with disease in 2 family members from 1 family (PMID: 33496845). The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse models, zebrafish model, rescue evidence, expression-level data; PMIDs: 31448880, 33496845, 38243601). Homozygous loss-of-function variants in mice result in significant hearing loss, as well as abnormally shaped and significantly reduced number of short stereocilia in hair cells. Mutant zebrafish exhibit abnormal stereocilia morphology in the inner ear as well as significant hearing loss. Rescue evidence indicates that wild-type CLRN2 has the ability to restore hearing and hair cell stereocilia structure in homozygous mutant mice. Expression-level evidence reveals cochlear expression of CLRN2 in mice. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hearing Loss GCEP on the meeting date 8/20/2025 (SOP Version 11).
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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