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
Counsyl RCV000020324 SCV000677942 likely pathogenic beta Thalassemia 2017-06-16 criteria provided, single submitter clinical testing
GeneReviews RCV000020324 SCV000040700 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000029953 SCV000052608 pathogenic Beta thalassemia intermedia 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
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 2018-11-12 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.
OMIM RCV000016718 SCV000036988 pathogenic Beta-plus-thalassemia 1984-07-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507151 SCV000601247 pathogenic not provided 2017-06-30 criteria provided, single submitter clinical testing

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