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

gnomAD frequency: 0.00003  dbSNP: rs33914668

Total submissions: 13

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	RCV000508360	SCV000603909	pathogenic	not provided	2023-11-27	criteria provided, single submitter	clinical testing	The HBB c.316-2A>G variant (also known as IVS-II-849 (A->G), rs33914668, Hbvar ID: 940) is reported in the literature in both homozygous and compound heterozygous individuals affected with beta(0) thalassemia (Antonarakis 1984, Atweh 1985, HbVar database and references therein). This variant is found on only three chromosomes (3/282432 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant abolishes the canonical splice acceptor site of intron 2, which is likely to disrupt gene function. Indeed, RNA analyses of patient cells carrying the c.316-2A>G variant suggest altered splicing and retention of sections of intron 3 in the mature mRNA (Antonarakis 1984, Atweh 1985). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html 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. PMID: 6583702 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. PMID: 2987809
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 Genetics, 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	2023-12-18	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 disruption of this splice site 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. This variant is present in population databases (rs33914668, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with autosomal recessive beta-thalassemia (PMID: 2123063, 6583702). It has also been observed to segregate with disease in related individuals. This variant is also known as IVSII-849A>G. ClinVar contains an entry for this variant (Variation ID: 21191). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in intron 2 (PMID: 6583702). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002504815	SCV002814163	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	2022-02-25	criteria provided, single submitter	clinical testing
Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	RCV003389313	SCV004101387	pathogenic	Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; Malaria, susceptibility to; Methemoglobinemia, beta-globin type; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB	2023-11-07	criteria provided, single submitter	clinical testing
OMIM	RCV000016701	SCV000036971	pathogenic	Beta zero thalassemia	1992-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000020336	SCV000040712	not provided	beta Thalassemia		no assertion 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
Natera, Inc.	RCV000020336	SCV002089190	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing