HBA1

Inheritance Pattern: AD

Disease ID:MONDO:0020835

Submitter: ClinGen

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 to *HBA1* was HbM-Iwate, which was genetically confirmed in 1999 (PMID: 10477710) in relation to autosomal dominant methemoglobineamia, alpha type. This variant occurs in the conserved proximal histidine residue, and is replaced by tyrosine. This type of amino acid substitution in the heme binding pocket causes structural alterations which stabilize the ferric state, resulting in extremely low oxygen affinity and resistance to reduction. This missense variant has been reported in 2 probands in 2 publications (PMIDs: 10477710, 25931326). 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 summary, there is limited evidence supporting the relationship between *HBA1* 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, *HBA1* 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.

Inheritance Pattern: AD

Disease ID:MONDO:0020835

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0011399

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0015579

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0011399

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0054802

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0020459

Submitter: ClinGen

*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).

Inheritance Pattern: AR

Disease ID:MONDO:0100561

Submitter: ClinGen

Alpha-thalassemia spectrum is known to be caused by inactivation of the alpha globin genes (*HBA1* and *HBA2*), with severity depending on how many of the 4 alleles are affected (PMID: 19678601). Patients with 1 allele inactivated in either *HBA1* or *HBA2* are unaffected carriers. Patients with 2 dysfunctional alleles between *HBA1* and *HBA2* have alpha-thalassemia trait with mild hypochromic microcytosis, usually with no significant clinical effect to the patient. Individuals with 3 alleles deleted or inactivated have Hemoglobin H (HbH) disease, which is characterized by more severe microcytosis, splenomegaly, and anemia. Loss of function of 4 alleles causes Hb Bart's disease, which leads to fatal hydrops fetalis (PMID: 29032940). Due to ClinGen’s framework in evaluating monogenic causes of disease, this curation focuses solely on association between *HBA1* variants and alpha-thalassemia under the disease entity, *HBA1*-related alpha-thalassemia spectrum (MONDO:0100561). The split curation for the association of *HBA2*-related alpha-thalassemia spectrum (MONDO:0100562) has been curated separately. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms, inheritance pattern, and phenotypic variability in alpha-thalassemia spectrum and other disease entities associated with the alpha globin genes. Therefore, the following disease entities have been split into multiple disease entities: unstable hemoglobin disease, hemoglobin M disease, familial erythrocytosis 7. Wilson et al. reported the first variant specifically in *HBA1* in 1977 (PMID: 909779). 6 variants (1 nonsense, 2 missense, 2 intronic, and 1 in-frame duplication of 6 amino acids) that have been reported in 7 probands in 5 publications (PMIDs:9657838, 25976776, 24111644, 32751969, 7803274) are included in this curation. The HB Groene Hart variant was recurrent in the literature, and was scored in 4 probands across 2 publications in this curation. In 3 probands, the variant was observed in the homozygous state (PMID: 24111644) while it was observed in compound heterozygosity with the c.70G>T (p.Glu24Ter) variant in 1 proband (PMID:32751969). A monomer shift assay including Hb Groene Hart with regularly-contacting proteins revealed impaired interaction with alpha hemoglobin stabilizing protein in addition to impaired interaction with β globin protein (PMID:19349619). More evidence is available in the literature demonstrating well-known deletional variants encompassing part or all of *HBA1* such as the alpha 3.7, 4.2, and 5.2 Kb deletions (PMID:6255436). Only probands demonstrating non-deletional *HBA1* variants have been scored. The mechanism of pathogenicity appears to be LOF. This gene-disease relationship is also supported by expression studies, protein interactions, biochemical evidence, and animal models. GTEx analysis of expression in normal human tissues revealed high expression specifically in whole blood, which is consistent with the hypothesized role of *HBA1* in hemoglobin (PMID:23715323). HBA1 protein interacts with the beta hemoglobin chain encoded by the HBB gene (PMID: 6644819), which can harbor variants associated with the closely related condition beta-thalassemia. Altering heme pocket residues on *HBA1* results in decreased affinity for NO, CO2, and O2, which is consistent with the hypothesized role of *HBA1* in binding and transporting oxygen (PMID:10390349). Radiation induced mutations in mice Hba1 resulted in phenotypes also seen in humans (hypochromic microcytic anemia, decreased MCV, erythrocytosis, reticulocytosis). The mouse model was downscored due to the inability of mice to demonstrate the digenic inheritance pattern seen in humans (PMID:879556). In summary, *HBA1* is definitively associated with autosomal recessive *HBA1*-related alpha-thalassemia. 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 the meeting date 2/27/24 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0011399

Submitter: Natera

Inheritance Pattern: SD

Disease ID:MONDO:0011399

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0018023

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0013512

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0054802

Submitter: ClinGen

*HBA1* was first reported in relation to autosomal dominant erythrocytosis 7 in 1966 (Clarache et al. 1966; PMID: 5913291). Erythrocytosis 7 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 7 relative to other disease entities associated with *HBA1*. Therefore, the following disease entities have been split into curations; AD erythrocytosis, AD and AR alpha-thalassemia, unstable hemoglobin disease, and methemoglobinemia. This curation addresses only AD erythrocytosis. This curation includes at least 8 missense and 1 indel variants reported in 9 probands with AD erythrocytosis in 9 publications (PMIDs: 5913291, 11123, 701083, 3973024, 3667323, 3142772, 14649314, 24200101, 28532286). Variants in this gene segregated with disease in 15 additional family members (PMID: 5913291). This gene disease association is also supported by experimental evidence including expression, biochemical function, and protein-protein interactions (PMIDs: 11747442, 6644819). 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 10/25/2023 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0007705

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0054802

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0007705

Submitter: PanelApp Australia