Total submissions: 10
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000506748 | SCV007539277 | pathogenic | not provided | 2025-10-01 | criteria provided, single submitter | clinical testing | Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 24986053, 20406103, 2917118, 28670940, 2393712, 8037197, 31890591, 9163586, 31286593) |
| Fulgent Genetics, |
RCV002496456 | SCV002811524 | 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 | 2021-09-10 | criteria provided, single submitter | clinical testing | |
| Natera, |
RCV000030003 | SCV002091587 | pathogenic | beta Thalassemia | 2025-08-06 | criteria provided, single submitter | clinical testing | The c.92+2T>C variant in HBB is a canonical splice donor site variant predicted to affect pre-mRNA splicing, which may result in an abnormal transcript and altered protein product. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. 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: 18976160). Given the available evidence, this variant is classified as Pathogenic. |
| ARUP Laboratories, |
RCV000506748 | SCV001156558 | pathogenic | not provided | 2025-07-28 | criteria provided, single submitter | clinical testing | The HBB c.92+2T>C variant (rs33956879, HbVar ID: 820), also known as IVS-I-2 (T>C), has been reported in an individual with HbS/beta(0) thalassemia (Gonzalez-Redondo 1989), and an individual with beta-thalassemia major (Kluge 2014). It was found in-trans with another pathogenic variant in both reported cases (Gonzalez-Redondo 1989, Kluge 2014). The c.92+2T>C variant is reported as pathogenic in ClinVar (Variation ID: 36334), and found in the general population with a low overall allele frequency of 0.002% (4/245978 alleles) in the Genome Aggregation Database. This variant abolishes the canonical splice donor site of intron 1, which is likely to disrupt gene function. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Gonzalez-Redondo J et al. Severe Hb S-beta zero-thalassaemia with a T----C substitution in the donor splice site of the first intron of the beta-globin gene. Br J Haematol. 1989; 71(1):113-7. PMID: 2917118 Kluge M et al. Beta-Thalassemia major resulting from compound heterozygosity for HBB: c.92+2T>C [formerly known as IVS-I-2 (T>C)] and a novel beta(0)-thalassemia frameshift mutation: HBB: c.209delG; p.Gly70Valfs*20. Hemoglobin. 2014; 38(4):292-4. PMID: 24986053 |
| Labcorp Genetics |
RCV000506748 | SCV000961460 | pathogenic | not provided | 2023-08-17 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 36334). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This sequence change affects a donor splice site in intron 1 of the HBB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). This variant is present in population databases (rs33956879, gnomAD 0.004%). Disruption of this splice site has been observed in individuals with beta thalassemia (PMID: 2200760, 24986053, 28366028, 28391758). |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000506748 | SCV000601327 | pathogenic | not provided | 2017-06-14 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000030003 | SCV000052658 | pathogenic | beta Thalassemia | 2021-07-08 | criteria provided, single submitter | clinical testing | Variant summary: HBB c.92+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. The variant allele was found at a frequency of 1.6e-05 in 251218 control chromosomes. c.92+2T>C has been reported in the literature in multiple individuals affected with Beta Thalassemia (Gonzalez-Redondo_1989, Bouhass_1990, Agouti_2008, IbnAyub_2010). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Dr. |
RCV005888729 | SCV006771420 | not provided | Nonpapillary renal cell carcinoma | no classification provided | in vitro | ||
| The ITHANET community portal, |
RCV000030003 | SCV001244439 | pathogenic | beta Thalassemia | 2019-11-25 | no assertion criteria provided | curation | |
| OMIM | RCV003991531 | SCV000036968 | pathogenic | Beta zero thalassemia | 1990-09-01 | no assertion criteria provided | literature only |