Submissions for variant NM_000518.5(HBB):c.92+5G>A

dbSNP: rs33915217

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030004	SCV000052659	pathogenic	beta Thalassemia	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Counsyl	RCV000030004	SCV000220579	likely pathogenic	beta Thalassemia	2014-08-06	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV001216321	SCV001388112	pathogenic	not provided	2023-05-24	criteria provided, single submitter	clinical testing	This sequence change falls in intron 1 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. ClinVar contains an entry for this variant (Variation ID: 15449). This variant is also known as IVS-1-5 (G>A) or IVS-I-5. This variant has been observed in individuals with beta thalassemia (PMID: 1917531, 2200760, 3021139, 23590658, 28366028; 10815781.). This variant is present in population databases (rs33915217, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.92+5G nucleotide in the HBB gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 6188062, 18294253, 19000664, 22392582, 23162295, 27263053). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 3671081).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001216321	SCV001477683	pathogenic	not provided	2023-07-03	criteria provided, single submitter	clinical testing	The HBB c.92+5G>A variant (rs33915217, HbVar ID: 822), also known as IVS-I-5 (G->A), is reported in the literature in multiple individuals affected with severe beta(+) thalassemia (Lapoumeroulie 1987, Muniz 2000, Perea 2004, HbVar database and references therein). This variant is listed in ClinVar (Variation ID: 15449), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Functional studies indicate that the variant causes aberrant splicing of the HBB RNA, leading to reduced production of full-length transcripts (Lapoumeroulie 1987). Based on the above information, the variant is classified as pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Lapoumeroulie C et al. Expression of a beta thalassemia gene with abnormal splicing. Nucleic Acids Res. 1987 15(20):8195-204. PMID: 3671081. Muniz A et al. Beta-thalassaemia in Cubans: novel allele increases the genetic diversity at the HBB locus in the Caribbean. Am J Hematol. 2000 64(1):7-14. PMID: 10815781. Perea F et al. Molecular spectrum of beta-thalassemia in the Mexican population. Blood Cells Mol Dis. 2004 33(2):150-2. PMID: 15315794.
Fulgent Genetics, Fulgent Genetics	RCV005049367	SCV005684715	pathogenic	Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; Malaria, susceptibility to; METHEMOGLOBINEMIA, BETA TYPE; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB	2024-04-25	criteria provided, single submitter	clinical testing
OMIM	RCV000016707	SCV000036977	pathogenic	Beta-plus-thalassemia	1986-09-14	no assertion criteria provided	literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000030004	SCV001244505	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000030004	SCV002091586	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing