Submission Details

ATP11A was first reported in relation to autosomal dominant nonsyndromic hearing loss in 2022 (Pater et al., PMID: 35278131). ATP11A-related hearing loss is slowly progressive, nonsyndromic, and sensorineural. Variants in ATP11A have been reported in individuals with the following disease entities: auditory neuropathy, autosomal dominant 2 (MIM: 620384), leukodystrophy, hypomyelinating, 24 (MIM:619851), and deafness, autosomal dominant 84 (MIM:619810). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, phenotypic variability, or inheritance pattern between auditory neuropathy, autosomal dominant 2 and deafness, autosomal dominant 84. Therefore, the disease entities have been lumped into one term, autosomal dominant nonsyndromic hearing loss. We have split out leukodystrophy, hypomyelinating, 24 and this will be addressed by a separate GCEP.

One intronic, one frameshift, and one large deletion variants that have been reported in four probands in two publications (PMIDs: 35278131, 36300302) are included in this curation. The mechanism of pathogenicity is unknown at this time, but the three known variants all caused splicing defects affecting the last or second to last exon, most likely leading to a truncated protein. This gene-disease relationship is also supported by expression studies, a conditional knock-out mouse model, and a loss of function zebrafish model; However, the model organisms may not recapitulate the mechanism of disease in humans, as the proposed mechanism in humans in haploinsufficiency (PMIDs: 36300302, 40223426). 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 May 21st, 2025 (SOP Version 11).