ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.92+1G>A (rs33971440)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000390929 SCV000329826 pathogenic not provided 2018-12-22 criteria provided, single submitter clinical testing The c.92+1G>A pathogenic variant in the HBB gene has been reported previously in association with beta-thalassemia (Faustino et al., 1992). This splice site variant destroys the canonical splice donor site in intron 1, resulting in a frameshift that removes the translation initiator Methionine codon. The c.92+1G>A variant is observed in 5/66,726 (0.0075%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). We interpret c.92+1G>A as a pathogenic variant.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000390929 SCV000601324 pathogenic not provided 2017-07-10 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000508514 SCV000603901 pathogenic not specified 2018-07-03 criteria provided, single submitter clinical testing The HBB c.92+1G>A variant(also known as IVS-I-1 G->A) is predicted to cause a loss of the canonical donor splice site and has been associated with beta(0) thalassemia in several patients (see HbVar link and references therein, Orkin 1982); therefore this variant is considered to be pathogenic. References: Link to HbVar database for IVS-I-1 (G -> A): Orkin S et al. Linkage of beta-thalassaemia mutations and beta-globin gene polymorphisms with DNA polymorphisms in human beta-globin gene cluster. Nature. 1982;296(5858):627-31.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000390929 SCV000700731 pathogenic not provided 2017-01-13 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763254 SCV000893891 pathogenic Beta-thalassemia, dominant inclusion body type; Fetal hemoglobin quantitative trait locus 1; Heinz body anemia; Hb SS disease; alpha Thalassemia; Susceptibility to malaria; beta Thalassemia; Methemoglobinemia, beta-globin type; Erythrocytosis 6, familial 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000390929 SCV000934096 pathogenic not provided 2019-12-26 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 1 of the HBB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs33971440, ExAC 0.009%). This variant has been observed in several individuals affected with HBB-related conditions (PMID: 28391758, 28366028, 2200760). This variant is also known in the literature as IVS-I-1(G>A). ClinVar contains an entry for this variant (Variation ID: 15436). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001004350 SCV001163285 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000020340 SCV001193941 pathogenic beta Thalassemia 2019-12-20 criteria provided, single submitter clinical testing NM_000518.4(HBB):c.92+1G>A(aka IVS-I-1) 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 1390250, 1634236 and 6188062. Classification of NM_000518.4(HBB):c.92+1G>A(aka IVS-I-1) 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.
Integrated Genetics/Laboratory Corporation of America RCV000020340 SCV001360654 pathogenic beta Thalassemia 2019-04-15 criteria provided, single submitter clinical testing Variant summary: HBB c.92+1G>A 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 5' splicing donor site. At least one publication reports experimental evidence confirming this prediction, demonstrating that this variant abolishes correct mRNA splicing (Treisman 1983). The variant allele was found at a frequency of 9.5e-05 in 251366 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HBB causing Beta Thalassemia Major (9.5e-05 vs 0.011). The variant, c.92+1G>A, was reported in the literature and in multiple databases as a common disease variant, found in several homozygous and compound heterozygous individuals affected with Beta Thalassemia Major (e.g. Faustino 1992, Shalitin 2005, Lahiry 2008). Seven 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.
OMIM RCV000016694 SCV000036964 pathogenic beta^0^ Thalassemia 1982-04-15 no assertion criteria provided literature only
GeneReviews RCV000020340 SCV000040716 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000020340 SCV001244435 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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