ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.316-2A>G (rs33914668)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508360 SCV000601283 pathogenic not provided 2017-06-30 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507861 SCV000603909 pathogenic none provided 2020-06-05 criteria provided, single submitter clinical testing The HBB c.316-2A>G variant, also known as IVS-II-849 (A->G), has been reported in patients with beta-thalassemia (Antonarakis 1984, Atweh 1985, HbVar database and references therein). Functional characterization of the variant indicates aberrant splicing of the beta globin RNA, resulting in a transcript containing sections of intron 3 (Antonarakis 1984, Atweh 1985). The variant is listed in the dbSNP variant database (rs33914668), and observed in the general population databases at a frequency of 0.02 percent in the 1000 Genomes Project, and 0.00082 percent in the Exome Aggregation Consortium database. The variant is located in the splice consensus sequence, and computational algorithms (GeneSplicer, Human Splicing Finder, MaxEntScan, MutationTaster, NetGene2, NNSplice, SpliceSiteFinder-like) predict the loss of the canonical splice acceptor, consistent with functional studies. Based on the above information, the variant is classified as pathogenic. REFERENCES Link to HbVar database for IVS-II-849 (A->G): http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=940 Antonarakis S et al. beta-Thalassemia in American Blacks: novel mutations in the 'TATA' box and an acceptor splice site. Proc Natl Acad Sci U S A. 1984; 81(4):1154-8. Atweh G et al. Beta-thalassemia resulting from a single nucleotide substitution in an acceptor splice site. Nucleic Acids Res. 1985; 13(3):777-90.
GeneDx RCV000508360 SCV000616737 pathogenic not provided 2021-02-09 criteria provided, single submitter clinical testing Canonical splice site variant expected to result in aberrant splicing, and published functional studies show this variant causes the production of an alternatively splice transcript which is not able to encode normal beta-globin (Antonarakis et al., 1984); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27251090, 2123063, 23348723, 30626236, 2987809, 6583702, 1427786, 21250876, 22563936, 22975760, 9342003, 32172616)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020336 SCV000697115 pathogenic beta Thalassemia 2018-09-18 criteria provided, single submitter clinical testing Variant summary: HBB c.316-2A>G 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. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3 acceptor site. Two publications report experimental evidence that this variant affects mRNA splicing (Antonarakis_1984, Atweh_1985). The variant allele was found at a frequency of 1.1e-05 in 276762 control chromosomes (gnomAD). The variant, c.316-2A>G, has been reported in the literature in multiple individuals affected with Beta Thalassemia (Bravo-Urquiola_2012, Codrington_1990, Antonarakis_1984, Atweh_1985, Huisman_1997). These data indicate that the variant is very likely to be associated with disease. Six 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.
Baylor Genetics RCV001004562 SCV001163646 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000020336 SCV001193944 pathogenic beta Thalassemia 2019-12-09 criteria provided, single submitter clinical testing NM_000518.4(HBB):c.316-2A>G 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-zero variant. Sources cited for classification include the following: PMID 21250876, 2987809 and 2123063. Classification of NM_000518.4(HBB):c.316-2A>G is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Invitae RCV000508360 SCV001403482 pathogenic not provided 2020-10-21 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 2 of the HBB gene. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 90 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals affected with beta-thalassemia and to segregate with disease in a family (PMID: 2123063, 6583702). This variant is also known as IVSII-849A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 21191). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with the activation of a cryptic splice site in intron 2 (PMID: 6583702). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000016701 SCV000036971 pathogenic beta^0^ Thalassemia 1992-09-01 no assertion criteria provided literature only
GeneReviews RCV000020336 SCV000040712 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000020336 SCV001244423 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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