Submissions for variant NM_000518.5(HBB):c.315+1G>A

gnomAD frequency: 0.00003  dbSNP: rs33945777

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255349	SCV000321763	pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Reported previously in association with beta-thalassemia and reported to result in abnormal RNA splicing (Nasouhipur et al., 2014; Poddighe et al., 2015; Treisman et al., 1982); This variant is associated with the following publications: (PMID: 25087612, 25525159, 25332589, 26193974, 7151176, 28391758, 32581362, 34272389, 11559936, 34426522, 9163586, 8091935, 31589614, 14555304)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255349	SCV000601271	pathogenic	not provided	2021-11-24	criteria provided, single submitter	clinical testing	The HBB c.315+1G>A pathogenic variant disrupts a canonical splice-donor site and interferes with normal splicing of the beta globin mRNA. The variant is associated with beta-zero thalassemia (, and PMID: 28391758 (2017), 26193974 (2015), 25332589 (2014), 7151176 (1982)).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000255349	SCV000603893	pathogenic	not provided	2023-11-27	criteria provided, single submitter	clinical testing	The HBB c.315+1G>A variant (rs33945777, HbVar ID: 884), also known as IVS-II-1 G>A, has been identified in multiple patients with beta-0 thalassemia in both the homozygous state and in heterozygotes with a second pathogenic HBB variant (Jalilian 2017, Oppenheim 1990, Treisman 1982, Wong 1986, HbVar database). This variant abolishes the canonical splice donor site of intron 2, and functional characterization indicates the absence of normally spliced transcripts and generation of small amounts of aberrantly spliced mRNA (Treisman 1982, Treisman 1983), consistent with computational predictions (Alamut v.2.11). The variant is reported as pathogenic in ClinVar (Variation ID: 15438) and is found in the general population with an overall allele frequency of 0.004% (11/282562 alleles) in the Genome Aggregation Database. Based on the above information, the variant is classified as pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Jalilian M et al. The Frequency of HBB Mutations Among ß-Thalassemia Patients in Hamadan Province, Iran. Hemoglobin. 2017 Jan;41(1):61-64. PMID: 28391758. Oppenheim A et al. Intrinsic potential for high fetal hemoglobin production in a Druz family with beta-thalassemia is due to an unlinked genetic determinant. Hum Genet. 1990 Dec;86(2):175-80. PMID: 1702403. Treisman R et al. A single-base change at a splice site in a beta 0-thalassemic gene causes abnormal RNA splicing. Cell. 1982 Jul;29(3):903-11. PMID: 7151176 Treisman R et al. Specific transcription and RNA splicing defects in five cloned beta-thalassaemia genes. Nature. 1983 Apr 14;302(5909):591-6. PMID: 6188062. Wong C et al. On the origin and spread of beta-thalassemia: recurrent observation of four mutations in different ethnic groups. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6529-32. PMID: 3462712.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020332	SCV000697106	pathogenic	beta Thalassemia	2016-05-03	criteria provided, single submitter	clinical testing	Variant summary: The HBB c.315+1G>A variant affects a conserved nucleotide located in a canonical splice-site. Mutation taster predicts damaging outcome for this variant along with 5/5 splice-tools via Alamut predicting this variant to completely abolish 5' splicing donor site. These predictions have been confirmed by a functional study (Treisman_1982) suggesting pathogenicity. The variant was found in 5/121204 control chromosomes at a frequency of 0.0000413, which does not exceed the estimated maximal expected frequency of a pathogenic HBB allele (0.0111803). Moreover, it was reported in several patients with BTHAL and thalassemia major further supporting pathogenicity. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000020332	SCV000746439	pathogenic	beta Thalassemia	2017-12-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002476979	SCV000893886	pathogenic	Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; alpha Thalassemia; Malaria, susceptibility to; Methemoglobinemia, beta-globin type; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB	2022-01-13	criteria provided, single submitter	clinical testing
Invitae	RCV000255349	SCV000958500	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 of the HBB gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs33945777, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with HBB-related conditions (PMID: 2446680, 23590658, 25332589, 27263053, 28391758). This variant is also known as IVS-II-1 (G>A). ClinVar contains an entry for this variant (Variation ID: 15438). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in insertion of the first 47 nucleotides of intron 2 between exons 2 and 3 or with exon 2 skipping and introduces a new termination codon (PMID: 7151176). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001004566	SCV001163650	pathogenic	Hb SS disease		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000020332	SCV001193967	pathogenic	beta Thalassemia	2019-12-04	criteria provided, single submitter	clinical testing	NM_000518.4(HBB):c.315+1G>A 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 1483699, 25332589, 7558878 and 1634368. Classification of NM_000518.4(HBB):c.315+1G>A 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.
Centogene AG - the Rare Disease Company	RCV000020332	SCV001426506	pathogenic	beta Thalassemia		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000020332	SCV001520749	pathogenic	beta Thalassemia	2019-09-12	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV000020332	SCV001810475	pathogenic	beta Thalassemia	2021-07-22	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001723572	SCV001950085	pathogenic	Dominant beta-thalassemia	2021-08-18	criteria provided, single submitter	clinical testing	This variant was identified as homozygous.
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001731303	SCV001984020	pathogenic	not specified	2020-05-14	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255349	SCV002024958	pathogenic	not provided	2023-03-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288502	SCV002581299	pathogenic	Beta-thalassemia HBB/LCRB	2022-02-17	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003987325	SCV004804905	pathogenic	Malaria, susceptibility to	2024-03-17	criteria provided, single submitter	research
OMIM	RCV000016696	SCV000036966	pathogenic	Beta zero thalassemia	1998-03-15	no assertion criteria provided	literature only
GeneReviews	RCV000020332	SCV000040708	not provided	beta Thalassemia		no assertion provided	literature only
College of Science, Al Muthanna University, Al Muthanna University	RCV000016696	SCV000864069	pathogenic	Beta zero thalassemia	2018-01-01	no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000020332	SCV001162252	pathogenic	beta Thalassemia		no assertion criteria provided	research
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000020332	SCV001244636	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000020332	SCV002089197	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing