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

dbSNP: rs33941377

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317048	SCV000919452	pathogenic	Beta thalassemia intermedia	2023-06-30	criteria provided, single submitter	clinical testing	Variant summary: HBB c.-137C>T is located in the untranscribed region upstream of the HBB gene region. The variant was absent in 31398 control chromosomes. 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). The following publications have been ascertained in the context of this evaluation (PMID: 2018842, 11857746, 21119755, 21423179, 20524821, 27821015, 1550780). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001379381	SCV001156633	pathogenic	not provided	2024-08-05	criteria provided, single submitter	clinical testing	The HBB c.-137C>T variant (rs33941377, HbVarID: 759), 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 the 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: https://globin.bx.psu.edu/hbvar/menu.html Gallagher PG et al. Mutation in a Highly Conserved COOH-Terminal Residue of Kruppel-Like Factor 1 Associated with Elevated Hb F in a Compound Heterozygous beta-Thalassemia Patient with a Nontransfusion-Dependent Thalassemia Phenotype. Hemoglobin. 2016 Sep;40(5):361-364. PMID: 27821015. 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. PMID: 2018842.
Baylor Genetics	RCV001004365	SCV001163303	pathogenic	Hb SS disease		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379381	SCV001577175	pathogenic	not provided	2024-02-22	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 is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with autosomal recessive beta-thalassemia (PMID: 2018842, 20524821, 27821015). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as -87C>T. ClinVar contains an entry for this variant (Variation ID: 36287). Studies have shown that this variant alters HBB gene expression (PMID: 2018842). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001379381	SCV005081124	pathogenic	not provided	2023-09-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, as transfection of the gene with c.-137C>T in HeLa cells showed a reduction of beta globin gene transcriptional activity (Kulozik et al., 1991; Kircher et al., 2019); Also known as -87C>T; No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 11857746, 2018842, 20524821, 31395865, 27821015, 9163586, 21119755, 21423179, 1550780)
Fulgent Genetics, Fulgent Genetics	RCV005049386	SCV005684742	likely pathogenic	Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; Malaria, susceptibility to; METHEMOGLOBINEMIA, BETA TYPE; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB	2024-06-04	criteria provided, single submitter	clinical testing
GeneReviews	RCV000445650	SCV000537283	not provided	beta Thalassemia		no assertion provided	literature only