ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.92+5G>C (rs33915217)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508244 SCV000603904 pathogenic not specified 2017-05-17 criteria provided, single submitter clinical testing
College of Science, Al Muthanna University,Al Muthanna University RCV000016705 SCV000864068 pathogenic Beta-plus-thalassemia 2018-01-01 no assertion criteria provided research
Counsyl RCV000020341 SCV000677988 pathogenic beta Thalassemia 2015-10-22 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255746 SCV000854898 pathogenic not provided 2018-05-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763253 SCV000893890 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
GeneDx RCV000255746 SCV000321761 pathogenic not provided 2018-12-20 criteria provided, single submitter clinical testing The c.92+5G>C variant in the HBB gene, categorized as a severe variant in the in Hb Var database (Patrinos et al., 2004), is one of the most common pathogenic variants in Middle Eastern and South Asian populations, associated with beta thalassemia major and beta thalassemia intermedia when in the homozygous or compound heterozygous state, opposite of a second HBB variant (Kazazian et al., 1984; Baysal, et al., 2011; Al-Allawi et al., 2013; Chaudhary et al., 2016). This variant reduces the quality of the splice donor site in intron 1, causing the adjacent exon 1 to be out of frame, potentially losing the first Methionine residue. When transfected into cultured cells, the c.92+5G>C variant showed reduced natural splice donor site activity, with the activation of three cryptic splice sites. The c.92+5G>C cells produced half as much RNA as the wild type cells (Treisman et al., 1983). The c.92+5G>C variant is observed in 81/16,510 (0.49%) alleles from individuals of South Asian background in the ExAC dataset (Lek et al., 2016). We interpret c.92+5G>C as a pathogenic variant.
GeneReviews RCV000020341 SCV000040717 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000020341 SCV000697156 pathogenic beta Thalassemia 2016-04-11 criteria provided, single submitter clinical testing Variant summary: The c.92+5G>C variant affects a non-conserved intronic nucleotide. Mutation taster predicts damaging outcome for this variant. 4/5 programs in Alamut predict a loss of canonical splicing donor site. ESE finder predicts that this variant may affect ESE site of SC35. This variant is found in 87/121280 control chromosomes at a frequency of 0.0007173, which does not exceed maximal expected frequency of a pathogenic allele (0.0111803). This variant has been reported in many affected individuals (both homozygotes and compound heterozygotes with another disease variant in trans) presented with phenotypes including BTHAL-MJR and BTHAL-ITM. Functional studies proved the aberrant RNA splicing products (Treisman_Nature_1983). In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant was classified as a Pathogenic.
Invitae RCV000255746 SCV000942942 pathogenic not provided 2018-10-02 criteria provided, single submitter clinical testing This sequence change falls in intron 1 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs33915217, ExAC 0.5%). This variant has been observed in numerous individuals and families affected with beta thalassemia and has been reported as a prevalent disease-associated variant in Pakistani and Indian populations (PMID: 27263053, 23162295, 22392582, 19000664, 18294253). This variant is also known as IVS-I-5, IVSI-5, and IVS1-5 in the literature. ClinVar contains an entry for this variant (Variation ID: 15447). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that transfected cells carrying this intronic change produce half as much RNA as wild-type cells (PMID: 6188062). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000016705 SCV000036975 pathogenic Beta-plus-thalassemia 1984-05-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255746 SCV000601328 pathogenic not provided 2017-07-10 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.