ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.92+2T>C (rs33956879)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000030003 SCV000052658 pathogenic beta Thalassemia 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506748 SCV000601327 pathogenic not provided 2017-06-14 criteria provided, single submitter clinical testing
Invitae RCV000506748 SCV000961460 pathogenic not provided 2018-09-28 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 not present in population databases (ExAC no frequency). Disruption of this splice site has been observed to be homozygous or in combination with another HBB variant in individuals affected with beta thalassemia (PMID: 24986053, 28391758, 28366028, 2200760). ClinVar contains an entry for this variant (Variation ID: 36334). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000120 SCV001156558 pathogenic not specified 2018-08-07 criteria provided, single submitter clinical testing The HBB c.92+2T>C variant (rs33956879), also known as IVS-I-2 (T>C), has been reported in an individual with HbS/beta(0) thalassemia (Gonzalez-Redondo 1989), and an individual with beta-thalassemia major (Kluge 2014). It was found in-trans with another pathogenic variant in both reported cases (Gonzalez-Redondo 1989, Kluge 2014). The c.92+2T>C variant is reported as pathogenic in ClinVar (Variation ID: 36334), and found in the general population with a low overall allele frequency of 0.002% (4/245978 alleles) in the Genome Aggregation Database. This variant abolishes the canonical splice donor site of intron 1, which is likely to disrupt gene function. Based on available information, this variant is considered to be pathogenic. REFERENCES Link to HbVar database for IVS-I-2 (T>C): Gonzalez-Redondo J et al. Severe Hb S-beta zero-thalassaemia with a T----C substitution in the donor splice site of the first intron of the beta-globin gene. Br J Haematol. 1989; 71(1):113-7. Kluge M et al. Beta-Thalassemia major resulting from compound heterozygosity for HBB: c.92+2T>C (formerly known as IVS-I-2 (T>C)) and a novel beta(0)-thalassemia frameshift mutation: HBB: c.209delG; p.Gly70Valfs*20. Hemoglobin. 2014; 38(4):292-4.
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000030003 SCV001244439 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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