HBB was first reported in relation to autosomal dominant erythrocytosis 6 in 1968 (Stamatoyannopoulos et al., PMID: 17795074). Erythrocytosis 6 is a disorder of the blood characterized by a high concentration of erythrocytes in the blood and an increased oxygen affinity of hemoglobin. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found differences in molecular mechanisms, inheritance pattern, and phenotypic variability in erythrocytosis 6 relative to other disease entities associated with HBB. Therefore, the following disease entities have been split into multiple curations; AD erythrocytosis, AD and AR beta-thalassemia, hemoglobin M disease, and unstable hemoglobin disease. This curation addresses only AD erythrocytosis. This curation includes at least 43 missense, 2 nonsense, and 1 indel variants reported in 46 probands with AD erythrocytosis in 25 publications (PMIDs: 17795074, 2363414, 2272838, 1814856, 12908805, 14649314, 15727901, 16282896, 16987804, 18818920, 21077764, 21250878, 23859443, 23859762, 24482100, 24200101, 27312559, 27651169, 27250824, 28332377, 31657650, 31132167, 32151172, 34167411, 35052472).
This gene disease association is also supported by experimental evidence including expression, biochemical function, protein-protein interactions, functional alteration of patient cells, and animal models (PMIDs: 11747442, 6644819, 3997804, 22203977). In summary, HBB is definitively associated with autosomal dominant erythrocytosis 6. 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 General Gene Curation Expert Panel on 9/27/2023 (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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