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

dbSNP: rs33913413

Total submissions: 13

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	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, Molecular Genetics and Genomics, 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.
Invitae	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.
CeGaT Center for Human Genetics Tuebingen	RCV000506607	SCV001961262	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000506607	SCV002023456	likely pathogenic	not provided	2021-06-11	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496382	SCV002813926	pathogenic	Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; alpha Thalassemia; Malaria, susceptibility to; Methemoglobinemia, beta-globin type; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB	2022-02-13	criteria provided, single submitter	clinical testing
GeneDx	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)
PreventionGenetics, part of Exact Sciences	RCV003398526	SCV004104878	pathogenic	HBB-related condition	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.
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
Natera, Inc.	RCV000984183	SCV002089192	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing