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

gnomAD frequency: 0.00005  dbSNP: rs33971440

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000390929	SCV000329826	pathogenic	not provided	2022-06-30	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Also described as IVS-I-1 (G> A) due to alternate nomenclature; This variant is associated with the following publications: (PMID: 25525159, 22975760, 2200760, 25087612, 23348723, 24777453, 21228398, 8602996, 6280057, 30843739, 1634236, 1390250, 28366028, 28391758, 27199182, 31718331, 34426522, 31589614, 9586437, 31890591, 9163586, 2577233)
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	RCV000390929	SCV000603901	pathogenic	not provided	2023-11-21	criteria provided, single submitter	clinical testing	The HBB c.92+1G>A variant (also known as IVS-I-1 G->A, rs33971440, HbVar ID: 817) 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: https://globin.bx.psu.edu/hbvar/hbvar.html 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. PMID: 6280057
Eurofins Ntd Llc (ga)	RCV000390929	SCV000700731	pathogenic	not provided	2017-01-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002476978	SCV000893891	pathogenic	Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; alpha Thalassemia; Malaria, susceptibility to; METHEMOGLOBINEMIA, BETA TYPE; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB	2022-04-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000390929	SCV000934096	pathogenic	not provided	2024-01-19	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. 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). This variant is present in population databases (rs33971440, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with HBB-related conditions (PMID: 2200760, 28366028, 28391758). 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. 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 Genetics, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Baylor Genetics	RCV001329338	SCV001520751	pathogenic	Fetal hemoglobin quantitative trait locus 1	2019-07-05	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000390929	SCV001714969	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000390929	SCV002024953	pathogenic	not provided	2023-12-21	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000020340	SCV002073260	pathogenic	beta Thalassemia		criteria provided, single submitter	clinical testing	The splice donor variant c.92+1G>A in HBB (NM_000518.5) has been reported in multiple individuals with beta thalassemia (Aldemir O et al; Thein SL et al). The variant has been reported in ClinVar as Pathogenic. This variant affects an invariant splice nucelotide and is predicted to affect protein function. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000020340	SCV002318784	pathogenic	beta Thalassemia	2022-03-22	criteria provided, single submitter	clinical testing	Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 28391758, 28366028, 2200760). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000955). The variant is in trans with the other variant. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
AiLife Diagnostics, AiLife Diagnostics	RCV000390929	SCV002502725	pathogenic	not provided	2022-03-23	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002288501	SCV002556999	pathogenic	Beta-thalassemia HBB/LCRB	2023-06-05	criteria provided, single submitter	clinical testing	The HBB c.92+1G>A variant is classified as Pathogenic (PVS1, PS4_Moderate, PP4) The HBB c.92+1G>A variant is located in a splice donor region. Computational predictions support a deleterious effect on splicing and a likely disruption of the protein reading frame and non-sense mediated decay of the resulting protein product (PVS1). One publication reports experimental evidence demonstrating that this variant abolishes correct mRNA splicing (PMID: 6188062). The variant has been reported in multiple cases with a clinical presentation of beta-thalassaemia, and homozygotes tend to be transfusion-dependent (PMID:27453201, 8602996, 2200760) (PS4_Moderate). The variant is rare in population databases (gnomAD allele frequency = 0.0052%; 8 het and 0 hom in 152224 sequenced alleles; highest frequency = 0.013%, Latino population) (PM2_Supp). The variant has been reported in dbSNP (rs33971440) and in the HGMD database: CS991412. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 15436). he clinical features of this case are highly specific for the HBB, the family history is consistent with the mode of inheritance of this condition and this patient has a well-defined syndrome with little overlap with other clinical presentations (PP4).
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000020340	SCV002573548	pathogenic	beta Thalassemia		criteria provided, single submitter	clinical testing	A heterozygous 5' splice site variation in intron 1 of the HBB gene that affects the invariant GT donor splice site of exon 1 was detected. The variant has previously been reported in patients with beta thalassemia. The observed variant has not been reported in the 1000 genomes and gnomAD databases and has a minor allele frequency of 0.04% in our internal database. The reference base is conserved across species.
MGZ Medical Genetics Center	RCV002288501	SCV002580415	pathogenic	Beta-thalassemia HBB/LCRB	2022-05-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV002288501	SCV004027659	pathogenic	Beta-thalassemia HBB/LCRB	2023-09-19	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM3_STR
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000390929	SCV004243388	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000020340	SCV004847536	pathogenic	beta Thalassemia	2022-11-03	criteria provided, single submitter	clinical testing	The c.92+1G>A variant in HBB (also known as IVS-I-1 G->A) has been reported in numerous individuals with beta thalassemia (selected references Faustino 1992 PMID: 1634236, Orkin 1982 PMID: 6280057, Jalilian 2017 PMID: 28391758, Aldemir 2014 PMID: 25155404). It has been reported in CLinVar (Variation ID 15436) and has been identified in 2/15288 Latino chromosomes by gnomAD (https://gnomad.broadinstitute.org). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the HBB gene is an established disease mechanism in autosomal recessive beta thalassemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PM2_Supporting, PVS1, PM3_Very Strong.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV002288501	SCV005051812	pathogenic	Beta-thalassemia HBB/LCRB	2024-02-01	criteria provided, single submitter	curation
OMIM	RCV000016694	SCV000036964	pathogenic	Beta zero thalassemia	1982-04-15	no assertion criteria provided	literature only
GeneReviews	RCV000020340	SCV000040716	not provided	beta Thalassemia		no assertion 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
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000390929	SCV001977967	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000390929	SCV001979685	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000020340	SCV002091590	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV002288501	SCV004041638	pathogenic	Beta-thalassemia HBB/LCRB	2023-10-09	no assertion criteria provided	clinical testing