Submissions for variant NM_000518.5(HBB):c.93-22_95del

dbSNP: rs193922563

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030009	SCV000052664	pathogenic	beta Thalassemia	2021-09-27	criteria provided, single submitter	clinical testing	Variant summary: HBB c.93-22_95del25 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: five predict the variant abolishes a 3 prime acceptor site, which has been confirmed by a functional study (Orkin_1983). This variant was absent in 251322 control chromosomes (gnomAD). c.93-22_95del25 has been reported in the literature in individuals affected with Beta Thalassemia (Orkin_1983, Adekile_2015). These data indicate that the variant is likely to be associated with disease. Three 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.
Invitae	RCV001052793	SCV001217019	pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing	This variant results in the deletion of part of exon 2 (c.93-22_95del) 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 not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with beta-thalassemia (PMID: 6190800, 20437613, 23637309, 26076396). This variant is also known as IVS-1, 25bp del. ClinVar contains an entry for this variant (Variation ID: 15442). Studies have shown that this variant alters HBB gene expression (PMID: 6190800). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001052793	SCV001813003	pathogenic	not provided	2022-07-08	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 6308558, 35467101, 6190800)
Revvity Omics, Revvity	RCV001052793	SCV002024952	pathogenic	not provided	2020-07-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001052793	SCV002049943	pathogenic	not provided	2023-01-13	criteria provided, single submitter	clinical testing	The HBB c.93-22_95del variant (also known as IVS-1 25 bp del, HbVarID: 974, rs193922563) is reported in the literature in several individuals with beta-thalassemia (Adekile 2015, Miri-Moghaddam 2016, Orkin 1983, HbVar database). This variant was found in three siblings of one family, all of whom also carried an additional pathogenic variant (Adekile 2015). This variant is also reported in ClinVar (Variation ID: 15442). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes 25 nucleotides and abolishes the canonical splice acceptor site of intron 1, which is likely to disrupt gene function. Indeed, RNA analyses of cells expressing this variant show a lack of properly spliced transcripts (Orkin 1983). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Adekile AD et al. Clinical and Molecular Characteristics of Non-Transfusion-Dependent Thalassemia in Kuwait. Hemoglobin. 2015;39(5):320-6. PMID: 26076396. Miri-Moghaddam E et al. Molecular Characterization of ß-Thalassemia Intermedia in Southeast Iran. Hemoglobin. 2016 Jun;40(3):173-8. PMID: 27117567. Orkin SH et al. Inactivation of an acceptor RNA splice site by a short deletion in beta-thalassemia. J Biol Chem. 1983 Jun 25;258(12):7249-51. PMID: 6190800.
Genetics and Molecular Pathology, SA Pathology	RCV002465489	SCV002556511	pathogenic	Beta-thalassemia HBB/LCRB	2020-07-03	criteria provided, single submitter	clinical testing	PVS1, PS3, PM2, PP4, PP5
Ambry Genetics	RCV002371773	SCV002687367	pathogenic	Inborn genetic diseases	2017-06-16	criteria provided, single submitter	clinical testing	The c.93-22_95del25 pathogenic mutation, located at the boundary of intron 1 and coding exon 2 of the HBB gene, results from a deletion of 25 nucleotides between nucleotide positions 93-22 and 95. This alteration is predicted to disrupt the canonical splice acceptor site sequence and result in the deletion of three nucleotides from coding exon 2. This alteration was reported in an Asian Indian individual with beta-thalassemia and was shown to abolish the normal splicing when expressed in HeLa cells (Orkin SH et al. J. Biol. Chem., 1983 Jun;258:7249-51). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice donor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation.
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001052793	SCV002818275	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
3billion	RCV002465489	SCV003841985	pathogenic	Beta-thalassemia HBB/LCRB	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000015442). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM	RCV000016700	SCV000036970	pathogenic	Beta zero thalassemia	1983-07-25	no assertion criteria provided	literature only
Natera, Inc.	RCV000030009	SCV001453784	pathogenic	beta Thalassemia	2020-09-16	no assertion criteria provided	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001731304	SCV001984021	pathogenic	not specified	2020-07-21	flagged submission	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV002465489	SCV004171643	pathogenic	Beta-thalassemia HBB/LCRB	2023-11-24	no assertion criteria provided	clinical testing