ClinVar Genomic variation as it relates to human health

Variant summary: HBB c.-122T>A (aka. -72T>A) affects a non-conserved nucleotide that is located in the untranscribed region upstream of the HBB gene region, affecting the conserved CCAAT box sequence. The variant allele was found at a frequency of 6.6e-06 in 150926 control chromosomes (gnomAD v3.1 genomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-122T>A has been reported in the literature in heterozygous state in individuals who were asymptomatic or had mild anemia, with laboratory values either normal or suggestive of beta-thalassemia carrier trait (e.g. Pirastru_2017, Xinh_2022). These reports do not provide unequivocal conclusions about association of the variant with Hemoglobinopathy. Publications also reported experimental evidence evaluating the variants impact on promotor function, and demonstrated decreased promoter activities, with activity values similar to other pathogenic variants (e.g. Pirastru_2017, Kircher_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31395865, 28503568, 35023007). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. In conclusion, further cases should be evaluated where this variant is found in homozygosity or compound heterozygous state with beta-thalassemia mutations, in order to determine the clinical significance of this variant. Based on the evidence outlined above, the variant was classified as uncertain significance.

In the published literature, the variant has been reported in a Vietnamese family with multiple members showing slightly elevated A2 and indices suggestive of Beta Thalassemia Minor (PMID: 28503568 (2017)). Functional studies report the variant is damaging to protein structure and/or function (PMIDs: 28503568 (2017) and 31395865 (2019)). Based on the available information, this variant is classified as likely pathogenic.

The HBB c.-122T>A variant (rs1272414751, HbVar ID: 3029), also known as -72 (T>A), is reported in the literature in individuals affected with beta thalassemia or in heterozygous carriers (Kircher 2019, Pirastru 2017, Xinh 2022, HbVar database), although it is not fully evident whether this variant can cause beta-thalassemia in homozygous or compound heterozygous fashion on the basis of existing literature. This variant is also reported in ClinVar (Variation ID: 869326) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in the conserved CCAAT box of the beta-globin gene promoter (Pirastru 2017), and functional analyses by luciferase reporter assay suggest a reduction in beta globin transcription, with a decrease ranging from approximately 18% (Kircher 2019) to 47% (Pirastru 2017). Based on available information, this variant is considered to be likely pathogenic. References: Kircher M et al. Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution. Nat Commun. 2019 Aug 8;10(1):3583. PMID: 31395865. Pirastru M et al. A Novel -72 (T?A) ß-Promoter Mutation Causing Slightly Elevated HbA2 in a Vietnamese Heterozygote. Biomed Res Int. 2017;2017:4537409. PMID: 28503568. Xinh PT et al. Spectrum of HBB gene mutations among 696 ß-thalassemia patients and carriers in Southern Vietnam. Mol Biol Rep. 2022 Apr;49(4):2601-2606. PMID: 35023007.