ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.-137C>A (rs33941377)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000445644 SCV000799290 likely pathogenic beta Thalassemia 2018-04-09 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763257 SCV000893894 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 RCV000445644 SCV000537285 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000029950 SCV000052605 likely pathogenic Beta thalassemia intermedia 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000781447 SCV000919483 likely pathogenic Hemoglobinopathy 2018-09-18 criteria provided, single submitter clinical testing Variant summary: HBB c.-137C>A is a conserved nucleotide located in the untranscribed region upstream of the HBB gene region in the CACCC functional element. The variant allele was found at a frequency of 9.7e-05 in 30974 control chromosomes. c.-137C>A has been reported in the literature in individuals affected with Beta Thalassemia Intermedia, indicating the variant may be associated with disease. At least one publication reports experimental evidence evaluating transcription levels, and showed the variant results in ~40% of normal activity (Myers_1986). In addition, other substitutions at the same nucleotide are known to be disease causing for BTHAL-intermedia (c.-137C>T and c.-137C>G). The C>T substitution results in a moderate reduction in transcription activity (Kulozik_1991), while the C>G substitution at the same nucleotide position showed significantly lower levels of RNA transcripts via RNA blotting and S1 Nuclease Mapping (Treisman_1983). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506877 SCV000601244 pathogenic not provided 2017-04-20 criteria provided, single submitter clinical testing

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