Submission Details

Hemoglobin M disease was first reported by Horlein and Weber in 1948 (PMID: 18105244) in a family with hereditary cyanosis due to methemoglobinemia. Chemical characterizations of hemoglobin M (Hb M) were described in the late 1950s and early 1960s by Gerald (PMIDs: 13572451, 13897827), who reported that Hbs M are poorly, or not at all, separable electrophoretically from normal adult hemoglobin unless the hemolysate has been treated with oxidizing agents and the isolated methemoglobins M differ in the spectral absorption curves. These chemical differences result in the methemoglobinemia known as Hemoglobin M disease, in which more than 1% of hemoglobin is oxidized to methemoglobin, a type of hemoglobin that contains the ferric form of iron, and patients are cyanotic but otherwise asymptomatic. The first variant specifically attributed in HBA2 was HbM-Iwate, which was genetically confirmed in 1995 (PMID: 7745837, 31327183) in relation to autosomal dominant Hemoglobin M disease. The two predominant missense variants occur in conserved proximal or distal histidine residues, which are replaced by tyrosine. These amino acid substitutions in the heme binding pocket cause structural alterations which stabilize the ferric state, resulting in extremely low oxygen affinity and resistance to reduction. Three missense variants have been reported in 6 probands in 6 publications (PMIDs: 7745837, 31327183, 25031065, 25725047, 31269924, 21637412) and are included in this curation. Hemoglobin M variants have altered function, suggesting a neomorphic mechanism of pathogenicity, due to increased stabilization of the ferric state. This gene-disease relationship is also supported by experimental evidence, the high specificity of expression within the whole blood (PMID: 23715323) and its well-established function in carrying oxygen, as part of the hemoglobin structure (PMID: 11747442). In Hemoglobin M disease, the function is altered due to differences in the heme structure (PMID: 4521212). In summary, there is limited evidence supporting the relationship between HBA2 and autosomal dominant methemoglobineamia, alpha type. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. The classification was approved by the ClinGen General GCEP on the meeting date July, 26, 2023 (SOP version 9). Of note, HBA2 is also related to alpha-thalassemia, erythrocytosis, Heinz body anemia, and Hemoglobin H disease, however per criteria outlined by the ClinGen Lumping and Splitting Working group we found differences in that the molecular mechanism (missense variants which stabilize the ferric state) and phenotype (benign cyanosis) were unique to the Hemoglobin M disease entity, which is therefore curated separately from the additional disease entities.