ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.316-197C>T

gnomAD frequency: 0.00005  dbSNP: rs34451549
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029984 SCV000052639 pathogenic Beta-thalassemia major 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000794203 SCV000603895 pathogenic not provided 2023-11-24 criteria provided, single submitter clinical testing The c.316-197C>T variant (also known as IVS-II-654 C->T, rs34451549, HbVar ID:889) has been reported in the compound heterozygous state in individuals with beta (+) thalassemia intermedia and in the homozygous state in a patient with transfusion-dependent beta-thalassemia major (see link to HbVar database and references therein, Lin 2013, Wu 2017). This variant is reported as pathogenic in ClinVar (Variation ID: 15458) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant, and computational algorithms (Alamut v.2.11) predict that this variant impacts splicing by creating a novel cryptic donor splice site. Additionally, functional mRNA studies of this variant demonstrate aberrant splicing that leads to the production of a transcript that contains a premature termination codon (Cheng 1984, Huang 1994). Based on available information, this variant is considered pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Cheng T et al. beta-Thalassemia in Chinese: use of in vivo RNA analysis and oligonucleotide hybridization in systematic characterization of molecular defects. Proc Natl Acad Sci U S A. 1984;81(9):2821-5. PMID: 6585831 Huang SZ et al. RNA transcripts of the beta-thalassaemia allele IVS-2-654 C-->T: a small amount of normally processed beta-globin mRNA is still produced from the mutant gene. Br J Haematol. 1994 Nov;88(3):541-6. PMID: 7819066 Lin M et al. Hemoglobinopathy: molecular epidemiological characteristics and health effects on Hakka people in the Meizhou region, southern China. PLoS One. 2013;8(2):e55024. PMID: 23383304 Wu L et al. B-thalassemia caused by compound heterozygous mutations and cured by bone marrow transplantation: A case report. Mol Med Rep. 2017 Nov;16(5):6552-6557. PMID: 28901454
Invitae RCV000794203 SCV000933597 pathogenic not provided 2024-01-21 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. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with beta-thalassemia (PMID: 2014803, 6585831, 8435318, 29695942). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS2+654C>T, IVS-II-654 (C>T). ClinVar contains an entry for this variant (Variation ID: 15458). Studies have shown that this variant results in inclusion of 73 nucleotides from intron 2 and introduces a new termination codon (PMID: 6585831). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001004565 SCV001163649 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000020334 SCV001193938 pathogenic beta Thalassemia 2019-12-09 criteria provided, single submitter clinical testing NM_000518.4(HBB):c.316-197C>T is classified as 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 2014803, 6585381 and 8435318. Classification of NM_000518.4(HBB):c.316-197C>T is based on the following criteria: This is a well-established pathogenic variant in the literature that 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 RCV000794203 SCV001813891 pathogenic not provided 2023-11-06 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect as cDNA sequencing of c.316-197C>T revealed the use of a new cryptic donor site, resulting in a transcript with exons 1,2,3, and nucleotides 580-652 of intron 3; this transcript corresponds to the major species identified by blot hybridization analysis of erythroid RNA of affected patients (PMID: 6585831); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26201722, 26086873, 27469621, 26084319, 21228398, 28943547, 30275481, 22975760, 20412082, 6585831, 26290351, 26865073, 23806067, 22335963, 20642335, 27117566, 25412720, 28901454, 31124576, 10222649, 9163586, 8091935, 8161731, 2143120, 28674233, 33092414)
Revvity Omics, Revvity Omics RCV000794203 SCV002024969 pathogenic not provided 2022-09-15 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003407341 SCV004115004 pathogenic HBB-related condition 2023-04-18 criteria provided, single submitter clinical testing The HBB c.316-197C>T variant is predicted to interfere with splicing. This variant, previously described as IVS2-654C>T, has been reported to alter splicing and be causative for beta thalassemia (Cheng et al 1984. PubMed ID: 6585831; Lin LI et al 1991. PubMed ID: 2014803; Kazazian HH Jr et al 1986. PubMed ID: 2875755 This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
OMIM RCV000016716 SCV000036986 pathogenic Beta zero thalassemia 1984-05-01 no assertion criteria provided literature only
GeneReviews RCV000020334 SCV000040710 not provided beta Thalassemia no assertion provided literature only
Natera, Inc. RCV000020334 SCV002089196 pathogenic beta Thalassemia 2017-03-17 no assertion criteria provided clinical testing

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