Total submissions: 14
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000029987 | SCV000052642 | pathogenic | Beta thalassemia intermedia | 2011-08-18 | criteria provided, single submitter | curation | Converted during submission to Pathogenic. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000506607 | SCV000601284 | pathogenic | not provided | 2021-12-15 | criteria provided, single submitter | clinical testing | The HBB c.316-3C>A pathogenic variant (also known as IVS-II-848 (C>A) is located adjacent to a canonical splice-acceptor site and interferes with normal HBB mRNA splicing (PMID: 2920213 (1989)). This variant has been reported to reduce the amount of normal beta-globin mRNA synthesized from the mutant allele, and is associated with beta-thalassemia (PMIDs: 2458145 (1988), 2920213 (1989), 25617386 (2015), 28276871 (2016), 31718331 (2020), and 32069775 (2020)). The frequency of this variant in the general population, 0.000062 (1/16256 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic. |
ARUP Laboratories, |
RCV000506607 | SCV001156554 | pathogenic | not provided | 2023-08-28 | criteria provided, single submitter | clinical testing | The HBB c.316-3C>A variant (rs33913413, HbVar ID: 901), commonly known as IVS-II-848C>A, is reported in the medical literature in individuals affected with beta+ thalassemia, either as a homozygous variant or a heterozygous variant in trans with another HBB variant (Atanasovska 2012, Elmezayen 2015, Gonzalez-Redondo 1988, Tuzmen 1997, Wong 1989, HbVar database). This variant is found on a single chromosome in the Genome Aggregation Database (1/250988 alleles), indicating it is not a common polymorphism. This is an intronic variant at a highly conserved nucleotide and computational algorithms (Alamut v.2.11) predict that this variant weakens the canonical splice acceptor site 5' of exon 3. In vitro functional studies have confirmed that this variant results in aberrant mRNA splicing, resulting in a longer transcript arising from a cryptic splice site 5' from the canonical site (Wong 1989). Based on available information, this variant is considered pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Atanasovska B et al. Molecular Diagnostics of ß-Thalassemia. Balkan J Med Genet. 2012 Dec;15(Suppl):61-5. PMID: 24052746. Elmezayen A et al. ß-Globin Mutations in Egyptian Patients With ß-Thalassemia. Lab Med. 2015;46(1):8-13. PMID: 25617386. Gonzalez-Redondo J 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. Tuzmen S et al. Rare beta-thalassemia mutation IVS-II-848 (C-A) first reported in a Turkish Cypriot family. Am J Hematol. 1997 Apr;54(4):338-9. PMID: 9092695. Wong C et al. Beta-thalassemia due to two novel nucleotide substitutions in consensus acceptor splice sequences of the beta-globin gene. Blood. 1989 Mar;73(4):914-8. PMID: 2920213. |
Labcorp Genetics |
RCV000506607 | SCV001392955 | pathogenic | not provided | 2024-01-02 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 2 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein. It affects a nucleotide within the consensus splice site. 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: 2458145, 2920213, 25617386, 28276871). 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 IVS-II-848. ClinVar contains an entry for this variant (Variation ID: 15451). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
Ce |
RCV000506607 | SCV001961262 | pathogenic | not provided | 2021-07-01 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV000506607 | SCV002023456 | likely pathogenic | not provided | 2021-06-11 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV002496382 | SCV002813926 | 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 | 2022-02-13 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000506607 | SCV004022798 | pathogenic | not provided | 2023-07-27 | criteria provided, single submitter | clinical testing | Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32069775, 25087612, 2458145, 2920213, 9140720, 25617386, 24985555, 25408857, 31718331, 9163586) |
Prevention |
RCV004528115 | SCV004104878 | pathogenic | HBB-related disorder | 2023-02-17 | criteria provided, single submitter | clinical testing | The HBB c.316-3C>A variant is predicted to interfere with splicing. The HBB gene variant c.316-3C>A, also reported as IVS-II-848 using legacy nomenclature, has been reported in multiple individuals with beta thalassemia (el-Kalla S et al 1997. PubMed ID: 9140720; Kurtoğlu A et al 2017. PubMed ID: 28276871; Elmezayen AD et al 2015. PubMed ID: 25617386; Gonzalez-Redondo et al 1988. PubMed ID: 2458145). The c.316-3C>A variant has also been interpreted as pathogenic by different laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/15451/). Together we classify the c.316-3C>A variant as pathogenic. |
Center for Genomic Medicine, |
RCV000506607 | SCV005090876 | pathogenic | not provided | 2024-07-31 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000016709 | SCV000036979 | pathogenic | Beta-plus-thalassemia | 1989-03-01 | no assertion criteria provided | literature only | |
Counsyl | RCV000984183 | SCV001132217 | likely pathogenic | beta Thalassemia | 2015-11-17 | no assertion criteria provided | clinical testing | |
The ITHANET community portal, |
RCV000984183 | SCV001244489 | pathogenic | beta Thalassemia | 2019-11-25 | no assertion criteria provided | curation | |
Natera, |
RCV000984183 | SCV002089192 | pathogenic | beta Thalassemia | 2017-03-17 | no assertion criteria provided | clinical testing |