ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000762846 SCV000893206 likely pathogenic Beta-thalassemia, dominant inclusion body type; Fetal hemoglobin quantitative trait locus 1; Heinz body anemia; Hb SS disease; alpha Thalassemia; Susceptibility to malaria; beta Thalassemia; METHEMOGLOBINEMIA, BETA TYPE; Erythrocytosis 6, familial 2018-10-31 criteria provided, single submitter clinical testing
GeneReviews RCV000445645 SCV000537282 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000781451 SCV000919487 pathogenic Hemoglobinopathy 2018-11-01 criteria provided, single submitter clinical testing Variant summary: HBB c.-138C>A is located in the untranscribed region upstream of the HBB gene region. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant lies in a known transcription binding site (CACCC box) where other HBB variants (such as c.-140C>T, c.-138C>T, c.-137C>G and c.-137C>T) are known to be pathogenic for BTHAL ITMD. The variant was absent in 30972 control chromosomes (gnomAD). The variant, c.-138C>A, has been reported in the literature in multiple individuals affected with Beta Thalassemia (Rund_1991, El-Shanshory_2014, Baysal_2011, Sirdah_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505872 SCV000601246 pathogenic not provided 2017-06-27 criteria provided, single submitter clinical testing

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