ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.-78A>C

dbSNP: rs33931746
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508592 SCV000605839 pathogenic not provided 2017-04-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589656 SCV000697148 pathogenic beta Thalassemia 2017-03-10 criteria provided, single submitter clinical testing Variant summary: The HBB c.-78A>C variant involves the alteration of a non-conserved nucleotide in the promoter region (transcriptional TATA box). One in silico tool predicts a damaging outcome for this variant. The variant of interest was observed in controls with an allele frequency of 0.0000322 (1/31018), which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant has been reported in multiple BTHAL-ITMD cases both as homozygotes and compound heterozygotes. In addition, multiple reputable databases classified this variant as pathogenic. Furthermore, another variant at this location, c.-78A>G has been reported and classified by LCA as "pathogenic," supporting the importance of this region/location for proper function. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as "Pathogenic."
Invitae RCV000508592 SCV000944281 pathogenic not provided 2023-05-19 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant alters HBB gene expression (PMID: 2987224, 24616209). ClinVar contains an entry for this variant (Variation ID: 15470). This variant is also known as -28 A>C. This variant has been observed in individual(s) with autosomal recessive HBB-related disease (PMID: 2200760, 8619407, 16103715, 17994378, 19960060). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This variant occurs in a non-coding region of the HBB gene. It does not change the encoded amino acid sequence of the HBB protein.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508592 SCV001156631 pathogenic not provided 2023-11-21 criteria provided, single submitter clinical testing The HBB c.-78A>C variant (rs33931746, HbVar ID: 768), also known as -28 (A>C), is reported in the literature in individuals affected with beta thalassemia (Agouti 2008, Gamarra 2009, Perea 1996, Poncz 1982, HbVar database) or in heterozygous carriers with microcytic anemia (Gamarra 2009, Perea 1996). In several individuals with beta thalassemia major, this variant was observed in trans to a beta-0 pathogenic variant (Gamarra 2009, Perea 1996). The c.-78A>C variant is located in the TATA box of the HBB gene (Poncz 1982), and functional analyses in transfected HeLa cells suggest it leads to a 2- to 3-fold decrease in beta globin transcription (Surrey 1985). Another variant at this position, c.-78A>G, is a common beta+ pathogenic variant that leads to a 3- to 5-fold reduction in HBB transcripts (Orkin 1983, Yamsri 2011). The c.-78A>C variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Agouti I et al. Molecular basis of beta-thalassemia in Morocco: possible origins of the molecular heterogeneity. Genet Test. 2008 Dec;12(4):563-8. PMID: 18976160. Gamarra S et al. beta-Thalassaemia Major in a Spanish Patient due to a Compound Heterozygosity for CD39 C > T/-28 A > C. Adv Hematol. 2009;2009:476342. PMID: 19960060. Orkin SH et al. ATA box transcription mutation in beta-thalassemia. Nucleic Acids Res. 1983; 11(14):4727-34. PMID: 6308558. Perea FJ et al. Haplotype analysis of the Mexican frameshift Cd 11 (-T) and -28 A->C beta-thalassemia alleles. Am J Hematol. 1996 Mar;51(3):240-2. PMID: 8619407. Poncz M et al. beta-Thalassemia in a Kurdish Jew. Single base changes in the T-A-T-A box. J Biol Chem. 1982 Jun 10;257(11):5994-6. PMID: 7076659. Surrey S et al. Functional analysis of a beta-globin gene containing a TATA box mutation from a Kurdish Jew with beta thalassemia. J Biol Chem. 1985 Jun 10;260(11):6507-10. PMID: 2987224. Yamsri S et al. Genotype and phenotype characterizations in a large cohort of beta-thalassemia heterozygote with different forms of alpha-thalassemia in northeast Thailand. Blood Cells Mol Dis. 2011; 47(2):120-4. PMID: 21664157.
Baylor Genetics RCV001004363 SCV001163301 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002482876 SCV002788217 pathogenic Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; alpha Thalassemia; Malaria, susceptibility to; Methemoglobinemia, beta-globin type; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB 2022-01-27 criteria provided, single submitter clinical testing
OMIM RCV000016728 SCV000036998 pathogenic Beta-plus-thalassemia 1982-06-10 no assertion criteria provided literature only
Counsyl RCV000589656 SCV000790517 pathogenic beta Thalassemia 2017-03-27 no assertion criteria provided clinical testing
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000589656 SCV001244523 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation
Natera, Inc. RCV000589656 SCV002091630 pathogenic beta Thalassemia 2018-11-06 no assertion criteria provided clinical testing

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