Submissions for variant NM_000518.5(HBB):c.93-1G>C

dbSNP: rs33943001

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506434	SCV000601335	pathogenic	not provided	2021-08-12	criteria provided, single submitter	clinical testing	The beta-globin (HBB) c.93-1G>C variant (also known as IVS-I-130 (G>C)) disrupts a canonical splice-acceptor site and interferes with normal HBB mRNA splicing. In the published literature, the variant is associated with beta(0)-thalassemia (PMIDs: 1517108 (1992), 1577489 (1992), 23510507 (2013), 26182339 (2015), 27828729 (2017)). The frequency of this variant in the general population, 0.000004 (1/251326 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375484	SCV001363915	pathogenic	Beta-thalassemia major	2021-04-01	criteria provided, single submitter	clinical testing	Variant summary: HBB c.93-1G>C 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: Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251326 control chromosomes (gnomAD). c.93-1G>C has been reported in the literature in multiple affected individuals (Sankaran_2011, Najmabadi_2002, el-Kalla_1997, Oner_1990, Hussain_2017). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506434	SCV001474478	pathogenic	not provided	2020-01-21	criteria provided, single submitter	clinical testing	The HBB c.93-1G>C variant (rs33943001), also known as IVS-I-130 (G>C), has been reported in individuals with beta-thalassemia trait when identified in a heterozygous state (He 2015, HbVar database and references therein), and beta thalassemia major when found in-trans with a truncating beta globin variant (Asadov 2013). It is listed as pathogenic in ClinVar (Variation ID: 439166), and observed once in the 1000 Genomes Project (1/5008 alleles), and once in the Genome Aggregation Database (1/246102 alleles). The variant is located in the splice consensus sequence, and computational algorithms (Mutation Taster, NNSplice, NetGene2, SpliceSiteFinder-like, MaxEntScan, GeneSplicer, Human Splicing Finder) predict it abolishes the canonical splice acceptor site. Based on the above information, the c.93-1G>C variant is classified as pathogenic. References: Link to HbVar database for IVS-I-130 (G>C): http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=831 Asadov C et al. Identification of two rare beta-globin gene mutations in a patient with beta-thalassemia intermedia from Azerbaijan. Hemoglobin. 2013; 37(3):291-6. He S et al. First Detection of a Splice Acceptor Site beta-Thalassemia Mutation: IVS-I-130 (HBB: c.93-1G > C) in a Chinese Patient. Hemoglobin.
Invitae	RCV000506434	SCV003439603	pathogenic	not provided	2022-12-16	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 439166). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is also known as IVS-I-130G>C. Disruption of this splice site has been observed in individuals with autosomal recessive beta thalassemia (PMID: 2283297, 9163586, 28391758, 28670940). This variant is present in population databases (rs33943001, gnomAD 0.003%). This sequence change affects an acceptor splice site in intron 1 of the HBB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309).
OMIM	RCV000016769	SCV000037039	pathogenic	Beta zero thalassemia	1992-05-01	no assertion criteria provided	literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV001078336	SCV001244514	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV001078336	SCV002089232	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing