ClinVar Genomic variation as it relates to human health

The HBB c.364G>T; p.Glu122Ter variant (also known as Glu121Ter when numbered from the mature protein or as Codon 121 (G->T), rs33946267, HbVar ID: 951) is reported in the literature in multiple individuals with clinical features varying from mild microcytic anemia to hemolytic anemia with splenomegaly and inclusion bodies (Divoka 2016, Fei 1989, Giordano 1998, Indrak 1992, Kazazian 1986, Stamatoyannopoulos 1974, Thein 1990). In at least one severely affected individual, this variant was not found in either parent and thus appears to have arisen de novo (Kazazian 1986). The p.Glu122Ter variant was reported in early studies to segregate in several families with a dominant form of beta-thalassemia with inclusion bodies (Fei 1989, Stamatoyannopoulos 1974, Thein 1990). However, later observations in heterozygous individuals with hematology consistent with beta-thalassemia trait suggested this variant may exhibit a more typical recessive inheritance pattern, but with a clinical presentation possibly made more severe due to additional genetic or environmental factors (Divoka 2016, Giordano 1998, Indrak 1992). This variant is reported in ClinVar (Variation ID: 15404) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the HBB gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein lacking 26 amino acids, several of which are essential for heme binding (Thein 1990). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Divoka M et al. Molecular Characterization of ß-Thalassemia in the Czech and Slovak Populations: Mediterranean, Asian and Unique Mutations. Hemoglobin. 2016 Jun;40(3):156-62. PMID: 26956563. Fei YJ et al. One form of inclusion body beta-thalassemia is due to a GAA----TAA mutation at codon 121 of the beta chain. Blood. 1989 Mar;73(4):1075-7. PMID: 2563949. Giordano PC et al. Phenotype variability of the dominant beta-thalassemia induced in four Dutch families by the rare cd121 (G-->T) mutation. Ann Hematol. 1998 Dec;77(6):249-55. PMID: 9875660. Indrak K et al. Molecular characterization of beta-thalassemia in Czechoslovakia. Hum Genet. 1992 Feb;88(4):399-404. PMID: 1740317. Kazazian HH Jr et al. Characterization of a spontaneous mutation to a beta-thalassemia allele. Am J Hum Genet. 1986 Jun;38(6):860-7. PMID: 3014870. Stamatoyannopoulos G et al. Inclusion-body beta-thalassemia trait. A form of beta thalassemia producing clinical manifestations in simple heterozygotes. N Engl J Med. 1974 Apr 25;290(17):939-43. PMID: 4361439. Thein SL et al. Molecular basis for dominantly inherited inclusion body beta-thalassemia. Proc Natl Acad Sci U S A. 1990 May;87(10):3924-8. PMID: 1971109.

Variant summary: HBB c.364G>T (p.Glu122X, also reported as p.Glu121X) is located in exon 3 (i.e. in the last exon) of the HBB gene. The current variant results in a premature termination codon that is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a C-terminal truncation, removing a part of the 147 amino acid long protein. A truncation downstream of this position has been classified as pathogenic for dominant B-THAL by our laboratory. The variant was absent in 282706 control chromosomes (gnomAD). c.364G>T has been reported in the literature in multiple individuals affected with considerable variation in phenotype, ranging from mild anemia to severe hemolytic anemia with splenomegaly (e.g. Kazazian_1986, Thein_1990, Giordano_1998). The variant segregated with the phenotype in a dominant manner, and the presence of inclusion bodies was also noted in several cases. In at least one of these reported individuals the variant likely occurred as a de novo event (Kazazian 1986). A publication reported the presence of a truncated protein product from a patient, however the amount of the truncated protein was very low, suggesting that this beta-globin variant is highly unstable and is mostly degraded soon after translation, although the presence of the truncated protein product, might also explain the presence of the frequently reported Heinz bodies (Adams_1990). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters have assessed the variant since 2014: all four classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic for dominant B-THAL.

The HBB c.364G>T (p.Glu122*) nonsense variant causes the premature termination of HBB protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been detected in multiple individuals with beta-thalassemia ranging from mild microcytic anemia to hemolytic anemia with splenomegaly and inclusion bodies (PMIDs: 4361439 (1974), 3014870 (1986), 2563949 (1989), 1971109 (1990), 1740317 (1992), 1517108 (1992), 9163586 (1997), 9875660 (1998), 24080465 (2013), 24265529 (2013), and 26956563 (2016)). Also, this variant has been reported to segregate in a dominant manner with the sever phenotype with presence of inclusion bodies in multiple families (PMIDs: 4361439 (1974), 2563949 (1989), 1971109 (1990), and 9875660 (1998)). In at least one of those severe cases, the variant was absent from parents and seemed to occur as a de novo event (PMID: 3014870 (1986)). Later studies suggested a more recessive pattern of inheritance for this variant with carriers showing more severe phenotype compared to a typical beta-thalassemia trait (PMIDs: 1740317 (1992) and 26956563 (2016)). While the variant is in the last exon and might skip nonsense-mediated decay, it is expected to create a truncated protein lacking 26 amino acids that are important to protein function (PMID: 1971109 (1990)). Based on the available information, this variant is classified as pathogenic.