ClinVar Genomic variation as it relates to human health

This variant interferes with polyadenylation of the alpha-2 globin mRNA and causes the synthesis of an extended alpha-2 globin mRNA transcript (PMID: 6646217 (1983), 3024968 (1986), and HbVar (http://globin.bx.psu.edu/cgi-bin/hbvar/counter)). The c.*94A>G variant is associated with alpha-thalassemia. Homozygosity for this variant is associated with Hb H disease (PMID: 7701914 (1994), 20507641 (2010), 25370869 (2014)).

Published functional studies demonstrate a damaging effect; specifically, the variant disrupts normal transcriptional termination and transcript polyadenylation and results in reduced levels of mature mRNA and HBA2 gene expression (Higgs et al., 1983; Whitelaw et al., 1986); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Variant aliases include: T, T-Saudi , poly A1 , PA-1; This variant is associated with the following publications: (PMID: 25370869, 16103716, 20301608, 28385057, 24826794, 29032940, 22686351, 19205971, 11480787, 1281602, 6646217, 3024968, 34272389, 29627922)

The HBA2 c.*94A>G variant (rs63751269, HbVar ID: 1070), also known as Poly A (A->G) or Hb T-Saudi, is reported in the literature in both homozygous individuals with an Hb H disease phenotype, and heterozygous carriers who were borderline microcytic and hypochromic without a significant anemia (Thein 1988, Yavarian 2005, HbVar and references therein). In addition, this variant has been observed in individuals affected with Hb H disease that also carried the pathogenic alpha -3.7 deletion (Yavarian 2005). The c.*94A>G variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is predicted to disrupt the conserved polyadenylation signal and result in an elongated transcript. Consistent with these predictions, functional assays indicate a disruption of normal transcriptional termination and transcript polyadenylation both in cultured cells and in patient samples, resulting in reduced levels of the mature mRNA (Higgs 1983, Whitelaw 1986). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Higgs DR et al. Alpha-thalassaemia caused by a polyadenylation signal mutation. Nature. 1983 Nov 24-30;306(5941):398-400. PMID: 6646217. Thein SL et al. The polyadenylation site mutation in the alpha-globin gene cluster. Blood. 1988 Feb;71(2):313-9. PMID: 3337900. Whitelaw E et al. Alpha-thalassaemia caused by a poly(A) site mutation reveals that transcriptional termination is linked to 3' end processing in the human alpha 2 globin gene. EMBO J. 1986 Nov;5(11):2915-22. PMID: 3024968. Yavarian M et al. Molecular basis of Hb H disease in southwest Iran. Hemoglobin. 2005;29(1):43-50. PMID: 15768554.

The c.*94A>G variant in HBA2, also known as Poly A (A->G) or Hb T-Saudi, has been reported in several (both homozygous as well as compound heterozygous (with a pathogenic variant in trans))individuals with an Hb H disease phenotype, and heterozygous carriers who were borderline microcytic and hypochromic without a significant anemia (Fei 1992 PMID: 1281602, Adekile 1994 PMID: 7701914, Thein 1988 PMID: 3337900, Yavarian 2005 PMID: 15768554, HbVar: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=1070 ). It has also been reported in ClinVar (Variation ID375749) and was absent from large population databases. This variant is predicted to disrupt the conserved polyadenylation signal and result in an elongated transcript. In vitro functional studies (both using cultured cells and patient samples) support an impact on protein function as they show a disruption of normal transcriptional termination and transcript polyadenylation, resulting in reduced levels of the mature mRNA (Higgs 1983 PMID: 6646217, Whitelaw 1986 PMID: 3024968). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Hb H disease. ACMG/AMP Criteria applied: PM3 Very strong, PM2_supporting, PS3_Moderate, PP3).