Submissions for variant NM_000518.5(HBB):c.-138C>T

gnomAD frequency: 0.00021  dbSNP: rs33944208

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507151	SCV000601247	pathogenic	not provided	2017-06-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781453	SCV000919489	pathogenic	Hemoglobinopathy	2018-11-08	criteria provided, single submitter	clinical testing	Variant summary: HBB c.-138C>T involves the alteration of a conserved nucleotide that is located in the untranscribed region upstream of the HBB gene region, in the promoter region. The variant allele was found at a frequency of 0.00026 in 30972 control chromosomes, predominantly observed within the African subpopulation at a frequency of 0.00092 in the gnomAD database. c.-138C>T has been reported in the literature in multiple individuals of African origin who were affected with Beta Thalassemia Intermedia and mixed heterozygous hemoglobinopathies (e.g. Orkin 1984, Beris 1992, Muniz 2000, Carrocini 2017, Silva 2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on mRNA expression, and demonstrated about a 3-5 times lower expression of the variant mRNA compared with the wild type (Orkin 1984). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as pathogenic (1x)/likely pathogenic(1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000507151	SCV000952151	pathogenic	not provided	2023-12-14	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 (rs33944208, gnomAD 0.09%). This variant has been observed in individual(s) with autosomal recessive beta thalassemia (PMID: 2458145, 27263053, 28385923). 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 -88C>T. ClinVar contains an entry for this variant (Variation ID: 15460). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects HBB function (PMID: 6086605). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507151	SCV001156564	pathogenic	not provided	2023-11-28	criteria provided, single submitter	clinical testing	The c.-138C>T variant (rs33944208, HbVar ID:756), also known as -88 C>T, has been reported in multiple patients with mild microcytic anemia (Orkin 1984, Wong 1986, Gonzalez-Redondo 1988), and has been found in-trans with other HBB pathogenic variants (Muniz 2000, Gonzalez-Redondo 1988, HbVar database). Functional characterization indicates that the variant alters the binding of transcription factors to the betaglobin promoter, and reduces the expression of HBB mRNA by 3 to 5 fold (Orkin 1984, HbVar database). This variant is found in the African population with an allele frequency of 0.09% (8/8708 alleles) in the Genome Aggregation Database. Based on the above information, the variant is classified as pathogenic. References: Link to HbVar database: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Gonzalez-Redondo JM et al. Clinical and genetic heterogeneity in black patients with homozygous beta-thalassemia from the southeastern United States. Blood. 1988 Sep;72(3):1007-14. PMID: 2458145. Muniz A et al. Beta-thalassaemia in Cubans: novel allele increases the genetic diversity at the HBB locus in the Caribbean. Am J Hematol. 2000 May;64(1):7-14. PMID: 10815781. Orkin SH et al. Base substitution at position -88 in a beta-thalassemic globin gene. Further evidence for the role of distal promoter element ACACCC. J Biol Chem. 1984 Jul 25;259(14):8679-81. PMID: 6086605. Wong C et al. On the origin and spread of beta-thalassemia: recurrent observation of four mutations in different ethnic groups. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6529-32. PMID: 3462712.
Myriad Genetics, Inc.	RCV000020324	SCV001194183	likely pathogenic	beta Thalassemia	2019-12-20	criteria provided, single submitter	clinical testing	NM_000518.4(HBB):c.-138C>T(aka -88C>T) is classified as likely pathogenic in the context of Hb beta chain-related hemoglobinopathy; it is associated with beta thalassemia and is classified as a beta-plus variant. Sources cited for classification include the following: PMID 2458145 and 6086605. Classification of NM_000518.4(HBB):c.-138C>T(aka -88C>T) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
GeneDx	RCV000507151	SCV002568726	pathogenic	not provided	2022-08-23	criteria provided, single submitter	clinical testing	Occurs in a non-coding region of the gene, upstream of the ATG translation start codon; Published functional studies demonstrate that this variant results in a reduction of beta-globin mRNA compared to wild type beta-globin (Orkin et al., 1984); Also known as -88C>T; This variant is associated with the following publications: (PMID: 28385923, 16732578, 22975760, 27263053, 7909640, 26202972, 28366028, 28670940, 9163586, 32172616, 31395865, 6086605, 26372288)
Ambry Genetics	RCV002390113	SCV002698365	pathogenic	Inborn genetic diseases	2017-04-21	criteria provided, single submitter	clinical testing	The c.-138C>T pathogenic mutation is located in the 5' untranslated region (5’ UTR) of the HBB gene. This pathogenic mutation results from a C to T substitution 138 bases upstream from the first translated codon. In one study, this mutation was detected in the homozygous state in 3 individuals with mild beta-thalassemia and in 2 individuals in conjunction with hemoglobin S (Gonzalez-Redondo JM et al. Blood, 1988 Sep;72:1007-14). In addition, in vitro studies showed a 3-5 times reduction in beta-globin RNA transcripts compared to wild type (Orkin SH et al. J. Biol. Chem., 1984 Jul;259:8679-81). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000016718	SCV000036988	pathogenic	Beta-plus-thalassemia	1984-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000020324	SCV000040700	not provided	beta Thalassemia		no assertion provided	literature only
Natera, Inc.	RCV000020324	SCV002091636	pathogenic	beta Thalassemia	2017-05-23	no assertion criteria provided	clinical testing