ClinVar Miner

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

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Total submissions: 11
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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 2017-04-05 criteria provided, single submitter clinical testing
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 TYPE; Erythrocytosis 6, familial 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000255349 SCV000958500 pathogenic not provided 2018-10-13 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.
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
Counsyl RCV000020332 SCV000678135 pathogenic beta Thalassemia 2015-06-06 no assertion criteria provided clinical testing
College of Science, Al Muthanna University,Al Muthanna University RCV000016696 SCV000864069 pathogenic beta^0^ Thalassemia 2018-01-01 no assertion criteria provided research

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