ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.-78A>C (rs33931746)

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Total submissions: 8
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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
Integrated Genetics/Laboratory Corporation of America 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 2019-09-16 criteria provided, single submitter clinical testing 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed to be homozygous or on the opposite chromosome (in trans) from several other pathogenic variants in individuals affected with HBB-related disease (PMID: 2200760, 8619407, 17994378, 19960060, 16103715). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. In the literature, this variant is also known as -28 A>C. ClinVar contains an entry for this variant (Variation ID: 15470). Experimental studies have shown that this promoter variant results in decreased binding of the TATA-binding protein and decreased transcription of the HBB mRNA (PMID: 2987224, 24616209). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000146 SCV001156631 pathogenic not specified 2019-04-10 criteria provided, single submitter clinical testing The HBB c.-78A>C variant (rs33931746), 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 general population databases (Exome Variant Server, 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 for c.-78A>C: 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. 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. Orkin SH et al. ATA box transcription mutation in beta-thalassemia. Nucleic Acids Res. 1983; 11(14):4727-34. 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. 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. 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. Yamsri S et al. Genotype and phenotype characterizations in a large cohort of beta-thalassemia heterozygote with different forms of a-thalassemia in northeast Thailand. Blood Cells Mol Dis. 2011; 47(2):120-4.
Baylor Genetics RCV001004363 SCV001163301 pathogenic Hb SS disease 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

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