Submissions for variant NM_000518.5(HBB):c.93-21G>A

gnomAD frequency: 0.00009  dbSNP: rs35004220

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030008	SCV000052663	pathogenic	Beta-thalassemia major	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000799079	SCV000603912	pathogenic	not provided	2023-11-24	criteria provided, single submitter	clinical testing	The HBB c.93-21G>A variant (rs35004220, ClinVar ID: 15454, HbVar ID: 827), also known as IVS-I-110 G>A, is reported in the literature in multiple individuals affected with beta+ thalassemia (Carrocini 2017, Hussain 2017, Jalilian 2017). This variant is one of the most common beta-thalassemia alleles in Mediterranean and Middle-Eastern countries (Kaplan 1990, HbVar database and references therein). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Carrocini GCS et al. Mutational Profile of Homozygous beta-Thalassemia in Rio de Janeiro, Brazil. Hemoglobin. 2017 Jan;41(1):12-15. PMID: 28366028. Hussain A et al. Rare beta-Globin Gene Mutations in Pakistan. Hemoglobin. 2017 Mar;41(2):100-103. PMID: 28670940. Jalilian M et al. The Frequency of HBB Mutations Among beta-Thalassemia Patients in Hamadan Province, Iran. Hemoglobin. 2017 Jan;41(1):61-64. PMID: 28391758. Kaplan F et al. Beta-thalassemia genes in French-Canadians: haplotype and mutation analysis of Portneuf chromosomes. Am J Hum Genet. 1990 46(1):126-32. PMID: 1967205.
Fulgent Genetics, Fulgent Genetics	RCV000763251	SCV000893888	pathogenic	Dominant beta-thalassemia; Fetal hemoglobin quantitative trait locus 1; Heinz body anemia; Hb SS disease; alpha Thalassemia; Malaria, susceptibility to; beta Thalassemia; Methemoglobinemia, beta-globin type; Erythrocytosis, familial, 6	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000799079	SCV000938726	pathogenic	not provided	2024-01-22	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. This variant is present in population databases (rs35004220, gnomAD 0.03%). This variant has been observed in individual(s) with HBB-related conditions (PMID: 1967205, 2200760, 28366028, 28391758). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS-I-110G>A. ClinVar contains an entry for this variant (Variation ID: 15454). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001004346	SCV001163281	pathogenic	Hb SS disease		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000020343	SCV001194010	pathogenic	beta Thalassemia	2019-10-18	criteria provided, single submitter	clinical testing	NM_000518.4(HBB):c.93-21G>A is classified as pathogenic and is associated with beta thalassemia. Sources cited for classification include the following: PMID 2200760, 1390250, 8330981, 1967205, 1390250, 2200760, 6264477, 6264391. Classification of NM_000518.4(HBB):c.93-21G>A is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000799079	SCV001248105	pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing	HBB: PM3:Very Strong, PM2, PP4, PS4:Supporting
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000799079	SCV001251768	pathogenic	not provided	2020-05-03	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262998	SCV001441067	pathogenic	Fetal hemoglobin quantitative trait locus 1	2019-01-01	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous.
Genome-Nilou Lab	RCV000020343	SCV001593262	pathogenic	beta Thalassemia	2021-05-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000799079	SCV001771181	pathogenic	not provided	2021-12-10	criteria provided, single submitter	clinical testing	In vitro RNA and functional studies demonstrate a damaging effect with the creation of an alternative splice site causing abnormal gene splicing (Busslinger et al., 1981).; Also known as IVS-I-110G>A; This variant is associated with the following publications: (PMID: 6264391, 21797703, 25087612, 22975760, 28670940, 27979672, 31456457, 31130284, 21228398, 26372288, 1967205, 26016902, 1390250, 6895866, 6264477, 28391758, 28366028, 28667000, 14555304, 9163586, 31589614, 15609277, 9629495, 12702481, 2577233)
Revvity Omics, Revvity	RCV000799079	SCV002024965	pathogenic	not provided	2021-12-27	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000020343	SCV002028326	pathogenic	beta Thalassemia	2021-04-06	criteria provided, single submitter	clinical testing
3billion	RCV000020343	SCV002318493	pathogenic	beta Thalassemia	2022-03-22	criteria provided, single submitter	clinical testing	The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 28391758, 28366028, 2200760). It was observed to be in trans with the other variant (3billion dataset). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000015454). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0001668). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
AiLife Diagnostics, AiLife Diagnostics	RCV000799079	SCV002501546	likely pathogenic	not provided	2021-06-24	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000799079	SCV002548814	pathogenic	not provided	2021-07-23	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002288504	SCV002556588	pathogenic	Beta-thalassemia HBB/LCRB	2020-01-17	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288504	SCV002581884	pathogenic	Beta-thalassemia HBB/LCRB	2022-08-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002371775	SCV002687366	pathogenic	Inborn genetic diseases	2015-08-31	criteria provided, single submitter	clinical testing	The c.93-21G>A pathogenic mutation (also known as IVS1-110G>A), located in coding intron 1 of the HBB gene, results from a G>A substitution 21 nucleotides before coding exon 2. This mutation was first described in an individual of Turkish Cypriot origin with severe thalassemia intermedia who was compound heterozygous for another pathogenic HBB mutation (Westaway D, Williamson R. Nucleic Acids Res. 1981;9:1777-1788). In a population of Turkish patients affected with beta thalassemia major, 33 individuals were homozygous for this pathogenic mutation and the allele frequency in some Turkish subpopulations is as high as 75% of disease alleles (Fettah A et al. Mediterr J Hematol Infect Dis. 2013;5(1):e2013055 and Baysal et al. Br J Haematol. 1992;81(4):607-9. ). RT-PCR studies from mRNA in both human samples and mouse models demonstrated the presence of aberrant splicing, with 90% of transcripts with abnormal splicing in homozygous mice (Vadolas J. J Biol Chem. 2006 Mar 17;281(11):7399-405). Based on the supporting evidence, c.93-21G>A is interpreted as a disease-causing mutation.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000020343	SCV003922245	pathogenic	beta Thalassemia	2023-05-02	criteria provided, single submitter	curation	The heterozygous c.93-21G>A variant in HBB was identified by our study in four affected members of one family with beta thalassemia. The c.93-21G>A variant in HBB has been identified in over 160 individuals with beta thalassemia (‚Äã‚ÄãPMID: 6264477, PMID: 6264391, PMID: 24106605, PMID: 28391758, PMID: 1390250, PMID: 2200760), but has been identified in 0.03% (37/128830) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs35004220). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 15454) and has been interpreted as pathogenic by multiple submitters. Of these 160 individuals, 138 were homozygotes (PMID: 1390250, PMID: 28391758, PMID: 24106605, PMID: 2200760), and 11 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 2200760, ClinVar Variation ID: 15436, ClinVar Variation ID: 15402, ClinVar Variation ID: 15457, ClinVar Variation ID: 15239; PMID: 6264391, ClinVar Variation ID: 15060; PMID: 24106605, ClinVar Variation ID: 15402, ClinVar Variation ID: 15415), which increases the likelihood that the c.93-21G>A variant is pathogenic. RT-PCR analysis of RNA from affected tissue shows evidence of altered splicing of exon 2, resulting in 19bp insertion, frameshift, and premature truncation (PMID: 16421096); altered splicing was also seen in HeLa cells (PMID: 6895866) and in a humanized mouse model (PMID: 16421096). This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PS3, PM2_Supporting, PM3_VeryStrong (Richards 2015).
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV002288504	SCV003929456	pathogenic	Beta-thalassemia HBB/LCRB		criteria provided, single submitter	clinical testing
OMIM	RCV000016712	SCV000036982	pathogenic	Beta-plus-thalassemia	1990-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000020343	SCV000040719	not provided	beta Thalassemia		no assertion provided	literature only
Pediatric Molecular Hematology, Schneider Children's Medical Center of Israel	RCV000020343	SCV000579457	pathogenic	beta Thalassemia		no assertion criteria provided	clinical testing
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000020343	SCV001244516	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000020343	SCV001453785	pathogenic	beta Thalassemia	2020-09-16	no assertion criteria provided	clinical testing