ATP2B2 was first reported in relation to autosomal dominant nonsyndromic hearing loss in 2018 (Smits et al., PMID: 30535804). This condition is characterized by early-onset/congenital hearing loss, which ranges in severity and is often progressive. 8 variants (nonsense, frameshift, splicing), many of which were de novo, that have been reported in at least 26 probands in 4 publications (PMIDs: 30535804, 33105617, 33111345, 36194208) are included in this curation. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (2 mouse models and functional alteration evidence; PMIDs: 9668038, 20826782). Mutant mouse models show significant hearing loss in both homozygous and heterozygous mutants. Other features seen in the mutants include lack of otoconia, structural ear anomalies, and impaired calcium homeostasis. Functional alteration evidence in Chinese Hamster Ovary cells shows impaired calcium homeostasis in the mutants. In summary, there is definitive evidence supporting the relationship between ATP2B2 and autosomal dominant nonsyndromic hearing loss. 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 Hearing Loss GCEP on the meeting date 06/18/2025 (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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