Total submissions: 11
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV006694356 | SCV007592671 | pathogenic | Beta-thalassemia HBB/LCRB | 2026-04-30 | reviewed by expert panel | curation | The c.-137C>G variant is located in the untranscribed region upstream of the HBB gene, in the CACCC functional element. The minor allele frequency in gnomAD v4.1 is 0.00001557 (11/706420 alleles), which is lower than the ClinGen Hemoglobinopathy VCEP threshold <0.0001 for PM2_Supporting, and therefore meets this criterion [PM2_P]. Two different variants, NM_000518.5(HBB):c.-137C>T and NM_000518.5(HBB):c.-137C>A [VCV000036287.6; VCV000036285.4], in the same base site are considered to have valid evidence for pathogenicity by the VCEP [PMID: 36453528] and have been classified as pathogenic for beta-thalassemia with a 2 star review status by ClinVar [PM5]. This variant has been reported in ≥15 unrelated individuals displaying a hematological phenotype consistent with beta thalassemia trait (reduced MCV and MCH with high HbA2), giving a total score of 16 [PS4_VS, PMID: 2917193; The Hemoglobinopathies Laboratory, Department of Human and Clinical Genetics, Leiden University Medical Center; Department of Medical Genetics, National and Kapodistrian University of Athens; Molecular Genetics Laboratory, Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences; Blood Disorder Genetics and Thalassemia Department, The Cyprus Institute of Neurology and Genetics]. This variant has been detected in 16 individuals with beta thalassemia requiring transfusions. Of those individuals, 14 were compound heterozygous for the variant and a pathogenic variant [IVS I-110 G>A; CD 39 C>T], confirmed in trans by DNA studies, and 2 individuals were homozygous for the variant. Total PM3 points are 15 [PM3_VS, PMID:2375912; 2917193; Molecular Genetics Laboratory, Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences; Blood Disorder Genetics and Thalassemia Department, The Cyprus Institute of Neurology and Genetics]. The variant has been reported to segregate with β-thalassemia (all had anemia, some with a history of transfusion) in 11 affected family members from 8 families. The total number of unaffected segregations is 1. The LOD score is >6.15. [PP1_S, PMID: 2917193; Molecular Genetics Laboratory, Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences]. The luciferase assay showed that the -87C>G allele reduces reporter gene expression by downregulating the β-globin gene promoter, indicating that this variant impacts protein function [PS3_P; PMID: 28503568]. The computational predictor CADD (PHRED score 14.94, VCEP threshold >12) suggests that this variant impacts HBB function [PP3]. In summary, this variant meets the criteria to be classified as a pathogenic variant for beta-thalassemia HBB/LCRB (MONDO:0013517) in an autosomal recessive manner based on the ACMG/AMP criteria applied, as specified by the ClinGen Hemoglobinopathy VCEP (specification version 1.0.0): PM3_VS, PS4_VS, PP1_S, PM5, PS3_P, PM2_P, PP3 |
| Fulgent Genetics, |
RCV002496385 | SCV002811544 | pathogenic | Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; alpha Thalassemia; Malaria, susceptibility to; METHEMOGLOBINEMIA, BETA TYPE; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB | 2022-04-06 | criteria provided, single submitter | clinical testing | |
| Natera, |
RCV000445653 | SCV002091635 | pathogenic | beta Thalassemia | 2025-10-31 | criteria provided, single submitter | clinical testing | The c.-137C>G variant in HBB is a 5' untranslated region (UTR) variant located upstream of the translation start codon. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 25902180). Given the available evidence, this variant is classified as Pathogenic. |
| Gene |
RCV000507653 | SCV001802934 | pathogenic | not provided | 2025-02-18 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect, as transcient transfection of the gene with c.-137C>G in Hela cells showed reduction of beta-globin mRNA production (PMID: 6086605); Also known as -87C>G using alternate nomenclature; No data available from control populations to assess the frequency of this variant; Located in a regulatory region; This variant is associated with the following publications: (PMID: 2446680, 6188062, 22975760, 6280057, 7655036, 28503568, 2837728, 291719, 21228398, 31395865, 38927598, 37816374, 2375912, 35336809, 9163586, 7507641, 39359944, 38322302, 28385923, 36054783, 6086605, 27821015, 39859286, 20704537, 28399358) |
| ARUP Laboratories, |
RCV000507653 | SCV001473053 | pathogenic | not provided | 2025-07-28 | criteria provided, single submitter | clinical testing | The HBB c.-137C>G variant (rs33941377, HbVar ID: 758), also known as -87 (C->G), is reported in the literature in multiple individuals affected with beta+ thalassemia (see HbVar database link and references therein, Orkin 1982). This variant is located in a conserved region of the beta globin gene promoter and functional analyses demonstrated a significant reduction in transcription (Treisman 1983). This variant is reported in ClinVar (Variation ID: 15464) and absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic. References: Orkin SH et al. Linkage of beta-thalassaemia mutations and beta-globin gene polymorphisms with DNA polymorphisms in human beta-globin gene cluster. Nature. 1982 Apr 15;296(5858):627-31. PMID: 6280057. Treisman R et al. Specific transcription and RNA splicing defects in five cloned beta-thalassaemia genes. Nature. 1983 Apr 14;302(5909):591-6. PMID: 6188062. |
| Myriad Genetics, |
RCV000445653 | SCV001194181 | likely pathogenic | beta Thalassemia | 2019-12-19 | criteria provided, single submitter | clinical testing | NM_000518.4(HBB):c.-137C>G(aka -87C>G) is classified as likely pathogenic in the context of Hb beta chain-related hemoglobinopathy and is associated with beta thalassemia. Sources cited for classification include the following: PMID 2446680, 2375912, 2917193 and 2837728. Classification of NM_000518.4(HBB):c.-137C>G(aka -87C>G) 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. |
| Labcorp Genetics |
RCV000507653 | SCV000939590 | pathogenic | not provided | 2023-07-13 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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 individuals with beta-thalassemia (PMID: 2375912, 2446680, 2917193). It has also been observed to segregate with disease in related individuals. This variant is also known as -87C>G. ClinVar contains an entry for this variant (Variation ID: 15464). 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: 2837728, 6188062). |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000507653 | SCV000601245 | pathogenic | not provided | 2025-05-20 | criteria provided, single submitter | clinical testing | The HBB c.-137C>G variant (also known as -87C>G) has been reported in the published literature to deleteriously affect the promoter and transcription of the beta globin (HBB) gene (PMIDs: 28503568 (2017), 2917193 (1989)). This variant is associated with beta(+)-thalassemia (HbVar (http://globin.bx.psu.edu/), and PMIDs: 28503568 (2017), 21228398 (2011), 2917193 (1989), 2446680 (1988), 6280057 (1982)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000029951 | SCV000052606 | pathogenic | Beta thalassemia intermedia | 2011-08-18 | criteria provided, single submitter | curation | Converted during submission from pathogenic to Pathogenic. |
| Gene |
RCV000445653 | SCV000537284 | not provided | beta Thalassemia | no classification provided | literature only | ||
| OMIM | RCV000016722 | SCV000036992 | pathogenic | BETA-PLUS-THALASSEMIA | 1982-04-15 | no assertion criteria provided | literature only |