ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.316-197C>T (rs34451549)

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Total submissions: 7
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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 RCV000508120 SCV000603895 pathogenic none provided 2020-07-31 criteria provided, single submitter clinical testing The c.316-197C>T variant (rs34451549), also known as IVS-II-654 C->T, 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 general population databases (Exome Variant Server, 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 for IVS-II-654 (C->T): 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. 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. 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. Wu L et al. Beta-thalassemia caused by compound heterozygous mutations and cured by bone marrow transplantation: A case report. Mol Med Rep. 2017 Nov;16(5):6552-6557.
Invitae RCV000794203 SCV000933597 pathogenic not provided 2020-10-06 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. This variant is a common cause of beta-thalasemia in China and Taiwan (PMID: 6585831, 2014803, 29695942, 8435318). This variant is also known as IVS2+654C>T, IVS-II-654 (C>T) in the literature. ClinVar contains an entry for this variant (Variation ID: 15458). Experimental studies have shown that this intronic change leads to an aberrant mRNA splicing that results in the inclusion of 73 nucleotides from intron 2 (PMID: 6585831). 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 Women's Health, 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.
OMIM RCV000016716 SCV000036986 pathogenic beta^0^ Thalassemia 1984-05-01 no assertion criteria provided literature only
GeneReviews RCV000020334 SCV000040710 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only

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