ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.316-3C>A (rs33913413)

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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 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 2017-06-30 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000119 SCV001156554 pathogenic none provided 2020-05-20 criteria provided, single submitter clinical testing The HBB c.316-3C>A variant (rs33913413), 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 for c.316-3C>A: Atanasovska B et al. Molecular Diagnostics of Beta-Thalassemia. Balkan J Med Genet. 2012 Dec;15(Suppl):61-5. Elmezayen A et al. Beta-Globin Mutations in Egyptian Patients With Beta-Thalassemia. Lab Med. 2015;46(1):8-13. 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. 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. 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.
Invitae RCV000506607 SCV001392955 pathogenic not provided 2020-02-21 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs33913413, ExAC 0.01%). This variant has been observed in individual(s) with beta-thalassemia (PMID: 2458145, 2920213, 25617386, 28276871). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS-II-848 in the literature. ClinVar contains an entry for this variant (Variation ID: 15451). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 2920213). For these reasons, this variant has been classified as Pathogenic.
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, The Cyprus Institute of Neurology and Genetics RCV000984183 SCV001244489 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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