HBA1 was first reported in relation to autosomal dominant unstable hemoglobin disease in 1963 (De Vries et al. 1963, PMID:14076130). Unstable hemoglobin disease results from the presence of a structurally abnormal hemoglobin variant which leads to Heinz bodies or basophilic inclusions in the red blood cells. The disease is characterized by hemolytic anemia, heat-labile hemoglobin, and is sometimes accompanied by splenomegaly and jaundice. The clinical severity and presentation of the unstable hemoglobinopathies vary widely. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms, inheritance pattern, and phenotypic variability in unstable hemoglobin disease and other disease entities associated with HBA1. Therefore, the following disease entities have been split into multiple disease entities: AD familial erythrocytosis 7, AD and AR alpha-thalassemia, AD hemoglobin M disease, and AD unstable hemoglobin disease. This curation addresses HBA1 in relation to AD unstable hemoglobin disease. At least 17 (13 missense, 1 nonsense and 3 deletion/insertion) variants that have been reported in 17 probands with AD unstable hemoglobin disease in publications (PMIDs: 14076130, 5643522, 902765, 108887, 7338471, 7275660, 7161109, 6547932, 2833478, 2574721, 2599879, 12972031, 19815833, 6526652) are included in this curation. This gene disease association is also supported by experimental evidence including expression pattern of HBA1 across human tissues which is highly specific within whole blood (PMID: 23715323), biochemical studies indicating the well-established function of HBA1 in oxygen binding (PMID: 11747442), and its protein-protein interaction with the beta hemoglobin chain encoded by the HBB gene (PMID: 6644819), which harbors variants associated with unstable hemoglobin disease. 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 General Gene Curation Expert Panel on 11/22/2023 (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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