Submissions for variant NM_000518.5(HBB):c.-82C>T

dbSNP: rs34500389

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507303	SCV000601322	pathogenic	not provided	2023-06-18	criteria provided, single submitter	clinical testing	The HBB c.-82C>T variant is located in the TATA-box in the promoter of the beta-globin gene. This variant is associated with beta(+) thalassemia, and has been observed in a screening study of individuals with hypochromic microcytic anemia and/or positive Hb profiles (PMID: 26715484 (2015)). Co-occurrence of this variant with Hb S results in a Hb S/beta+ thalassemia phenotype (PMID: 17486493 (2007)). A functional study showed this variant had near normal HBB promoter activity, however the result is inconclusive since other known deleterious variants in the promoter also showed similar activities (PMID: 31395865 (2019)). An additional study indicated this variant results in a small 1.5 fold increase in binding affinity to TATA-binding proteins, the physiological effects of which are uncertain (PMID: 33092544 (2020)). Previous names for this variant include -32 (C>T). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855594	SCV000697151	uncertain significance	not specified	2024-06-10	criteria provided, single submitter	clinical testing	Variant summary: HBB c.-82C>T (also described as -32C>T in the literature) affects a non-conserved nucleotide that is located in the untranscribed region, one nucleotide upstream to the conserved ATAAA sequence (i.e. the TATA box) therefore, it could affect gene expression. A saturation mutagenesis study reported that this variant had no significant effect on gene expression (Kircher_2019). While another study predicted that this variant changes the HBB TATA box sequence to a more canonical form (i.e. CATAAA to TATAAA) and the authors also demonstrated that the variant resulted in an increased in vitro affinity for TATA-binding protein (TBP) in electrophoretic mobility shift assay (EMSA), concluding that carriers of this variant may be susceptible to mild thalassemia because of the elevated amount of synthesized beta-chains (Ponomarenko_2020). The variant was absent in 31390 control chromosomes (gnomAD). The variant, c.-82C>T has been reported in the literature in an infant who also carried the HbS variant (c.20A>T (p.Glu7Val)) with a hemoglobin pattern suggestive of beta+ thalassemia (Eng_2007), and was also reported in individuals with abnormal hematological findings found during screening, but without specifying the exact phenotype and genotype (Hoppe_2013, Wang_2015). These data do not allow clear conclusions about association of the variant with Beta Thalassemia. The following publications have been ascertained in the context of this evaluation (PMID: 17486493, 23590658, 26715484, 22122796, 31395865, 33092544, 32033288, 33734896). Based on the evidence outlined above, the variant was classified as VUS.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507303	SCV004563892	uncertain significance	not provided	2023-03-28	criteria provided, single submitter	clinical testing	The HBB c.-82C>T variant (also known as -32 (C>T), rs34500389, HbVar ID: 2536) is reported in the literature in individuals with abnormal hematological findings, but the exact phenotype is unclear (Eng 2007, Hoppe 2013, Wang 2015). This variant is reported in ClinVar (Variation ID: 439163) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant occurs in the 5' untranslated region, one nucleotide upstream of the ATAA box of the beta globin promoter. However, in vitro assays are conflicting on the effects of the variant on TATA-binding protein affinity and gene expression (Kircher 2019, Ponomarenko 2020). Due to conflicting information, the clinical significance of the c.-82C>T variant is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Eng B. Three new beta-globin gene promoter mutations identified through newborn screening. Hemoglobin. 2007;31(2):129-34. PMID: 17486493. Hoppe CC. Prenatal and newborn screening for hemoglobinopathies. Int J Lab Hematol. 2013 Jun;35(3):297-305. PMID: 23590658. 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. Ponomarenko M et al. Unannotated single nucleotide polymorphisms in the TATA box of erythropoiesis genes show in vitro positive involvements in cognitive and mental disorders. BMC Med Genet. 2020 Oct 22;21(Suppl 1):165. PMID: 33092544. Wang S et al. Mutation screening for thalassaemia in the Jino ethnic minority population of Yunnan Province, Southwest China. BMJ Open. 2015 Dec 29;5(12):e010047. PMID: 26715484.
Fulgent Genetics, Fulgent Genetics	RCV005049577	SCV005684739	uncertain significance	Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; Malaria, susceptibility to; METHEMOGLOBINEMIA, BETA TYPE; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB	2024-04-25	criteria provided, single submitter	clinical testing
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV001078343	SCV001244530	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV001078343	SCV002091633	uncertain significance	beta Thalassemia	2017-09-26	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732913	SCV005366060	likely pathogenic	HBB-related disorder	2024-05-29	no assertion criteria provided	clinical testing	The HBB c.-82C>T variant is located in the 5' untranslated region. This variant was reported in an individual with beta thalassemia (Eng et al. 2007. PubMed ID: 17486493). Functional studies of this variant indicated that the expression effect on HBB was not significant, and the promoter activity was 0.96 of wildtype levels (Supplementary Table 10, Kircher et al. 2019. PubMed ID: 31395865). Of note, other variants in the promoter region of HBB have been reported in individuals with beta thalassemia (Eng et al. 2007. PubMed ID: 17486493; Ropero et al. 2017. PubMed ID: 28385923; Supplementary Table 10, Kircher et al. 2019. PubMed ID: 31395865). This variant has not been reported in a large population database, indicating it is rare. In ClinVar, this variant has conflicting interpretations including uncertain significance (3) and pathogenic (2) (https://www.ncbi.nlm.nih.gov/clinvar/variation/439163/). Taken together, we interpret this variant to be likely pathogenic.