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 reported in HBB was HbM-Hyde Park, which was identified as substitution of the proximal Histidine for Tyrosine in the late 1960s (PMID: 5700302) and genetically confirmed in 1992 (PMID: 1398295) in relation to autosomal dominant Hemoglobin M disease. The majority of the variants occur in the E or F-helices, most commonly involving conserved proximal or distal histidine residues. 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. Six missense variants that have been reported in 28 probands in 21 publications (PMIDs: 1398295, 6311728, 7663000, 7713749, 8226097, 8294206, 9494043, 15929117, 19199228, 19727720, 19758826, 24744675, 25079170, 28096792, 31267164, 31431070, 33251782, 34092029, 34789072, 34789072, 30828177) 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 oxygen binding, as part of the hemoglobin structure (PMID: 11747442). In Hemoglobin M disease, the function is altered due to differences in the heme structure (PMID: 15222763) and in patient cells alterations in the light absorption pattern explain the formation of chocolate-brown blood (PMID: 1398295). In summary, there is definitive evidence supporting the relationship between HBB and autosomal dominant Hemoglobin M disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen General GCEP on the meeting date July, 26, 2023 (SOP version 9).

Of note, HBB is also related to beta-thalassemia, sickle cell, erythrocytosis, and unstable hemoglobin 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.