ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 none provided 2020-06-17 criteria provided, single submitter clinical testing The HBB c.-137C>T variant (rs33941377), also known as -87C>T, is reported in the literature in several individuals with beta thalassemia intermedia, both of whom carried an additional pathogenic variant (Kulozik 1991, Gallagher 2016, HbVar database). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant is located in HBB promoter in the CACCC box that promotes gene transcription, and functional assays indicate that this variant results in reduced transcriptional activity (Kulozik 1991). Based on available information, this variant is considered pathogenic. References: 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 Gallagher PG et al. Mutation in a Highly Conserved COOH-Terminal Residue of Krüppel-Like Factor 1 Associated with Elevated Hb F in a Compound Heterozygous ß-Thalassemia Patient with a Nontransfusion-Dependent Thalassemia Phenotype. Hemoglobin. 2016 Sep;40(5):361-364. 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
Invitae RCV001379381 SCV001577175 likely pathogenic not provided 2020-09-13 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 in combination with another HBB variant in individuals with beta-thalassemia (PMID: 20524821, 2018842, 27821015). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. The variant is also known as -87C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 36287). This variant has been reported to affect HBB protein function (PMID: 2018842). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneReviews RCV000445650 SCV000537283 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only

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