ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.92+1G>T (rs33971440)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506724 SCV000603902 pathogenic not specified 2017-03-23 criteria provided, single submitter clinical testing
Counsyl RCV000169505 SCV000220968 likely pathogenic beta Thalassemia 2014-12-18 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000507580 SCV000854929 pathogenic not provided 2018-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169505 SCV000697154 pathogenic beta Thalassemia 2016-08-02 criteria provided, single submitter clinical testing Variant summary: The HBB c.92+1G>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant and 4/5 splice prediction tools predict a significant impact on normal splicing resulting in the reduction or complete loss of a splice donor site. This variant was found in 6/121330 control chromosomes at a frequency of 0.0000495, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). The variant has been reported in numerous affected individuals (homozygote and compound heterozygotes) in the literature ranging from mild to severe phenotype. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000507580 SCV000961403 pathogenic not provided 2018-10-08 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 1 of the HBB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs33971440, ExAC 0.04%). This variant has been observed in many individuals affected with beta thalassemia (PMID: 9450794, 22335963, 25849334, 27263053, 29695942). It is commonly reported in individuals of South Asian ancestry (PMID: 9450794, 22335963, 27263053). This variant is also known as IVS1-1 G-T in the literature. ClinVar contains an entry for this variant (Variation ID: 15437). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000016695 SCV000036965 pathogenic beta^0^ Thalassemia 2017-02-27 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507580 SCV000601325 pathogenic not provided 2017-07-10 criteria provided, single submitter clinical testing

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