Submissions for variant NM_000518.5(HBB):c.-140C>T

gnomAD frequency: 0.00004  dbSNP: rs34999973

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000029954	SCV000220248	likely pathogenic	beta Thalassemia	2014-04-15	criteria provided, single submitter	literature only
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001069376	SCV001156634	pathogenic	not provided	2023-10-04	criteria provided, single submitter	clinical testing	The HBB c.-140C>T variant (rs34999973, HbVar ID: 754), also known as -90C>T, is reported in the literature in multiple individuals with hematological profiles consistent with beta-thalassemia minor (Faustino 1992, Jia 2003, Prajantasen 2014, Shaji 2003, Yan 2015) and has been reported in trans to a pathogenic HBB variant in an individual with beta-thalassemia intermedia (Prajantasen 2014). This variant is reported in ClinVar (Variation ID: 15514). It is only found on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant occurs in the HBB promoter in a conserved CACCC box necessary for efficient transcription (Myers 1986). In vitro assays show that the variant disrupts binding of an EKLF transcription factor to the CACCC box in the promoter (Faustino 1996) and results in decreased HBB expression (Jia 2003). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Faustino P et al. beta-Thalassemia mutation at -90C-->T impairs the interaction of the proximal CACCC box with both erythroid and nonerythroid factors. Blood. 1996 Oct 15;88(8):3248-9. Faustino P et al. Novel promoter and splice junction defects add to the genetic, clinical or geographic heterogeneity of beta-thalassaemia in the Portuguese population. Hum Genet. 1992 Jul;89(5):573-6. Jia S et al. A rare beta-thalassaemia mutation (C-T) at position -90 of the beta-globin gene discovered in a Chinese family. Haematologica. 2003 Oct;88(10):1191-3. Myers RM et al. Fine structure genetic analysis of a beta-globin promoter. Science. 1986 May 2;232(4750):613-8. Prajantasen T et al. Molecular characterization of a beta-thalassemia intermedia patient presenting inferior vena cava thrombosis: interaction of the beta-globin erythroid Kruppel-like factor binding site mutation with Hb E and alpha(+)-thalassemia. Hemoglobin. 2014;38(6):451-3. Shaji RV et al. Rapid detection of beta-globin gene mutations and polymorphisms by temporal temperature gradient gel electrophoresis. Clin Chem. 2003 May;49(5):777-81. Yan JM et al. Heterozygous beta-thalassemia with complete absence of hemoglobin A2 in a Chinese adult. Int J Lab Hematol. 2015 Dec;37(6):e147-9.
Invitae	RCV001069376	SCV001234540	pathogenic	not provided	2023-12-10	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 present in population databases (rs34999973, gnomAD 0.02%). This variant has been observed in individual(s) with autosomal recessive beta thalassemia (PMID: 25370867, 27828729). 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 -90C>T. ClinVar contains an entry for this variant (Variation ID: 15514). Studies have shown that this variant alters HBB gene expression (PMID: 8874232, 14555318). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001069376	SCV001784385	likely pathogenic	not provided	2019-11-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate this variant significantly reduces promoter activity of the HBB protein compared to wild-type (Faustino et al., 1996; Kircher et al., 2019); This variant is associated with the following publications: (PMID: 32885601, 30275481, 27615034, 30626236, 27263053, 30489691, 29124982, 30277083, 28865746, 28669403, 21538688, 31395865, 20301599, 21119755, 18339318, 12709369, 8874232, 26096776, 25370867, 1634236, 25525159, 18294253, 14555318, 31411089, 18076350)
Illumina Laboratory Services, Illumina	RCV002260510	SCV002540254	pathogenic	HBB-Related Disorders	2022-03-04	criteria provided, single submitter	clinical testing	The HBB c.-140C>T variant occurs in an intron and results in the substitution of a cytosine at nucleotide position c.-140 with a thymine. Across a selection of the available literature, the c.-140C>T variant, also referred to as c.-90C>T variant in the literature, has been reported in multiple individuals with mild beta-thalassemia (Faustino et al. 1992; Shaji et al. 2003; Li et al. 2008; Yasmeen et al. 2016; Qian et al. 2020; Origa et al. 2021) and in a compound heterozygous state in an individual with beta-thalassemia intermedia (Prajantasen et al. 2014). The highest frequency of this allele in the Genome Aggregation Database is 0.00012 in the African/African-American population (version 3.1.2). The c.-140C>T variant resides in the proximal CACCC box of the 13-globin gene promoter and in vitro experiments in HeLa cells suggest that the variant resulted in an eightfold decrease of the transcription level of the reporter gene compared to the wild-type promoter. Furthermore, mutant cells show impaired binding of EKLF to CACCC box compared to cells expressing wild-type promoter (Faustino et al. 1996; Kircher et al. 2019). Based on the available evidence, the c.-140C>T variant is classified as pathogenic for HBB-related disorders.
MGZ Medical Genetics Center	RCV002288506	SCV002580414	pathogenic	Beta-thalassemia HBB/LCRB	2022-05-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001069376	SCV002774343	pathogenic	not provided	2021-06-23	criteria provided, single submitter	clinical testing	The variant found in at least one symptomatic individual. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. The variant has been shown to be damaging to protein function(s) relevant to disease mechanism. The variant has been shown to be statistically associated with disease in multiple families.
OMIM	RCV000016778	SCV000037048	pathogenic	Beta-plus-thalassemia	1992-07-01	no assertion criteria provided	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000202364	SCV000052609	pathogenic	Beta thalassemia intermedia	2015-11-08	no assertion criteria provided	clinical testing
GeneReviews	RCV000029954	SCV000537281	not provided	beta Thalassemia		no assertion provided	literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000029954	SCV001244600	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation