ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.-140C>T (rs34999973)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000029954 SCV000220248 likely pathogenic beta Thalassemia 2014-04-15 criteria provided, single submitter literature only
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000149 SCV001156634 pathogenic not specified 2018-09-27 criteria provided, single submitter clinical testing The HBB c.-140C>T variant (rs34999973), also known as c.-90C>T, is reported in the literature in multiple individuals with hematological profiles consistent with beta-thalassemia minor (Faustino 1992, Jia 2003, Prajantasen 2014, Shaji 2003, Yan 2015) and has been reported in trans to a pathogenic HBB variant in an individual with beta-thalassemia intermedia (Prajantasen 2014). This variant is reported as pathogenic/likely pathogenic by several laboratories in ClinVar (Variation ID: 15514), and it is found on only two chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant occurs in the HBB promoter in a conserved CACCC box necessary for efficient transcription (Myers 1986). In vitro assays show that the variant disrupts binding of an EKLF transcription factor to the CACCC box in the promoter (Faustino 1996) and results in decreased HBB expression (Jia 2003). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar entry: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=754 Faustino P et al. beta-Thalassemia mutation at -90C-->T impairs the interaction of the proximal CACCC box with both erythroid and nonerythroid factors. Blood. 1996 Oct 15;88(8):3248-9. Faustino P et al. Novel promoter and splice junction defects add to the genetic, clinical or geographic heterogeneity of beta-thalassaemia in the Portuguese population. Hum Genet. 1992 Jul;89(5):573-6. Jia S et al. A rare beta-thalassaemia mutation (C-T) at position -90 of the beta-globin gene discovered in a Chinese family. Haematologica. 2003 Oct;88(10):1191-3. Myers RM et al. Fine structure genetic analysis of a beta-globin promoter. Science. 1986 May 2;232(4750):613-8. Prajantasen T et al. Molecular characterization of a beta-thalassemia intermedia patient presenting inferior vena cava thrombosis: interaction of the beta-globin erythroid Kruppel-like factor binding site mutation with Hb E and alpha(+)-thalassemia. Hemoglobin. 2014;38(6):451-3. Shaji RV et al. Rapid detection of beta-globin gene mutations and polymorphisms by temporal temperature gradient gel electrophoresis. Clin Chem. 2003 May;49(5):777-81. Yan JM et al. Heterozygous beta-thalassemia with complete absence of hemoglobin A2 in a Chinese adult. Int J Lab Hematol. 2015 Dec;37(6):e147-9.
Invitae RCV001069376 SCV001234540 pathogenic not provided 2019-01-16 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. This variant has been observed in individuals affected with beta thalassemia (PMID: 25370867, 27828729). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as -90C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 15514). This variant has been reported to affect transcriptional activity of the HBB gene (PMID: 8874232, 14555318). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000016778 SCV000037048 pathogenic Beta-plus-thalassemia 1992-07-01 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000202364 SCV000052609 pathogenic Beta thalassemia intermedia 2015-11-08 no assertion criteria provided clinical testing
GeneReviews RCV000029954 SCV000537281 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000029954 SCV001244600 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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