ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000781433 SCV000919452 pathogenic Hemoglobinopathy 2017-10-30 criteria provided, single submitter clinical testing Variant summary: The c.-137C>T in HBB gene (a.k.a. -87C>T) is a 5UTR change that involves a highly conserved nucleotide and alters a promoter of this gene. This variant was found in 9/36060 control chromosomes at a frequency of 0.0002496, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). Ithanet lists this variant in association with + phenotype with relative carrier frequencies as follow: Czech Republic 2%, Slovakia 2%, Germany 1%, United Kingdom 0.2%, Italy 0.1%, and India 0.04%. The variant was found in multiple patients with symptoms ranging from beta-thalassemia major to beta-thalassemia intermedia depending on the second variant in trans and/or presence of alteration in genes encoding a-chain. Functional studies have shown that this variant leads to reduced transcription rate and synthesis of HBB (Kulozik_1991). Taking together, the variant was classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000148 SCV001156633 pathogenic not specified 2018-07-06 criteria provided, single submitter clinical testing The HBB c.-137C>T variant (also known as -87C>T), has been previously described in the literature in an individual with late onset symptoms and moderate anemia, who carried an additional pathogenic variant on the opposite chromosome (Kulozik 1991, see HbVar link). This variant is listed in ClinVar (Variation ID: 36287), and observed in the general population databases (rs33941377) at frequencies of 0.02 percent (1/5008 alleles; 1000 Genomes Project) and 0.01 percent (3/30974 alleles; Genome Aggregation Database). This variant is located in a conserved region of the beta globin gene promoter and is predicted to cause disease. Taken together this variant is considered pathogenic. REFERENCES Link to ClinVar database for c.-137C>T: https://www.ncbi.nlm.nih.gov/clinvar/variation/36287/ Link to HbVar database for c.-137C>T: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=759&.cgifields=histD Kulozik AE et al. Thalassemia intermedia: moderate reduction of beta globin gene transcriptional activity by a novel mutation of the proximal CACCC promoter element. Blood. 1991 May 1;77(9):2054-8.
Baylor Genetics RCV001004365 SCV001163303 pathogenic Hb SS disease criteria provided, single submitter clinical testing
GeneReviews RCV000445650 SCV000537283 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only

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