ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.315+1G>A (rs33945777)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255349 SCV000321763 pathogenic not provided 2018-12-21 criteria provided, single submitter clinical testing The c.315+1G>A pathogenic variant in the HBB gene has been 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 splice site variant destroys the canonical splice donor site in intron 2. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.315+1G>A variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.315+1G>A as a pathogenic variant.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255349 SCV000601271 pathogenic not provided 2017-06-30 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506249 SCV000603893 pathogenic not specified 2018-08-10 criteria provided, single submitter clinical testing The HBB c.315+1G>A variant (rs33945777), 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% (11/276896 alleles) in the Genome Aggregation Database. Based on the above information, the variant is classified as pathogenic. References: Link to HbVar database for c.315+1G>A: Jalilian M et al. The Frequency of HBB Mutations Among Beta-Thalassemia Patients in Hamadan Province, Iran. Hemoglobin. 2017 Jan;41(1):61-64. 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. 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. Treisman R et al. Specific transcription and RNA splicing defects in five cloned beta-thalassaemia genes. Nature. 1983 Apr 14;302(5909):591-6. 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.
Integrated Genetics/Laboratory Corporation of America 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 RCV000763249 SCV000893886 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 RCV000255349 SCV000958500 pathogenic not provided 2019-11-17 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in the last intron (intron 2) of the HBB gene. While this is not anticipated to result in nonsense mediated decay, it alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs33945777, ExAC 0.02%). This variant has been observed in several individuals affected with HBB-related conditions (PMID: 28391758, 2446680, 27263053, 23590658, 25332589). This variant is also known as IVS-II-1 (G>A) in the literature. ClinVar contains an entry for this variant (Variation ID: 15438). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant has a deleterious effect on splicing (PMID: 7151176). 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 Women's Health, 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.
OMIM RCV000016696 SCV000036966 pathogenic beta^0^ Thalassemia 1998-03-15 no assertion criteria provided literature only
GeneReviews RCV000020332 SCV000040708 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
College of Science, Al Muthanna University,Al Muthanna University RCV000016696 SCV000864069 pathogenic beta^0^ 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

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