ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.-138C>T (rs33944208)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507151 SCV000601247 pathogenic not provided 2017-06-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781453 SCV000919489 pathogenic Hemoglobinopathy 2018-11-08 criteria provided, single submitter clinical testing Variant summary: HBB c.-138C>T involves the alteration of a conserved nucleotide that is located in the untranscribed region upstream of the HBB gene region, in the promoter region. The variant allele was found at a frequency of 0.00026 in 30972 control chromosomes, predominantly observed within the African subpopulation at a frequency of 0.00092 in the gnomAD database. c.-138C>T has been reported in the literature in multiple individuals of African origin who were affected with Beta Thalassemia Intermedia and mixed heterozygous hemoglobinopathies (e.g. Orkin 1984, Beris 1992, Muniz 2000, Carrocini 2017, Silva 2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on mRNA expression, and demonstrated about a 3-5 times lower expression of the variant mRNA compared with the wild type (Orkin 1984). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as pathogenic (1x)/likely pathogenic(1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000507151 SCV000952151 pathogenic not provided 2019-12-23 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 to be homozygous or in combination with another HBB variant in individuals affected with beta thalassemia (PMID: 2458145, 27263053, 28385923). This variant is also known as -88C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 15460). Experimental studies have shown that this non-coding change causes reduced HBB gene expression (PMID: 6086605). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000125 SCV001156564 pathogenic not specified 2018-09-24 criteria provided, single submitter clinical testing The HBB c.-138C>T variant, also known as -88 C>T, has been reported in multiple patients with mild microcytic anemia (Gonzalez-Redondo 1988, Orkin 1984, Wong 1986), and has been found in-trans with other HBB pathogenic variants (Gonzalez-Redondo 1988, Muniz 2000, HbVar database). Functional characterization indicates that the variant alters the binding of transcription factors to the beta globin promoter, and reduces the expression of HBB mRNA by 3 to 5 fold (Orkin 1984, HbVar database). REFERENCES Link to HbVar database for -88 C>T: Gonzalez-Redondo J et al. Clinical and genetic heterogeneity in black patients with homozygous beta-thalassemia from the southeastern United States. Blood. 1988; 72(3):1007-14. Muniz A et al. Beta-thalassaemia in Cubans: novel allele increases the genetic diversity at the HBB locus in the Caribbean. Am J Hematol. 2000; 64(1):7-14. Orkin S et al. Base substitution at position -88 in a beta-thalassemic globin gene. Further evidence for the role of distal promoter element ACACCC. J Biol Chem. 1984; 259(14):8679-81. Wong C et al. On the origin and spread of beta-thalassemia: recurrent observation of four mutations in different ethnic groups. Proc Natl Acad Sci U S A. 1986; 83(17):6529-32.
Myriad Women's Health, Inc. RCV000020324 SCV001194183 likely pathogenic beta Thalassemia 2019-12-20 criteria provided, single submitter clinical testing NM_000518.4(HBB):c.-138C>T(aka -88C>T) is classified as likely pathogenic in the context of Hb beta chain-related hemoglobinopathy; it is associated with beta thalassemia and is classified as a beta-plus variant. Sources cited for classification include the following: PMID 2458145 and 6086605. Classification of NM_000518.4(HBB):c.-138C>T(aka -88C>T) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
OMIM RCV000016718 SCV000036988 pathogenic Beta-plus-thalassemia 1984-07-01 no assertion criteria provided literature only
GeneReviews RCV000020324 SCV000040700 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only

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