ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.316-146T>G (rs35328027)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029979 SCV000052634 pathogenic beta Thalassemia 2018-02-12 criteria provided, single submitter clinical testing Variant summary: HBB c.316-146T>G (Legacy Name: IVS-II-705 (T->G)) is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Three predict the variant strengthens a cryptic 5' donor site and one predicts the variant creates a 3' acceptor site. Gorman_1998 states "In the thalassemic IVS2705 human b-globin gene, a T-to-G mutation at position 705 of intron 2 improves the match of the surrounding sequence to the consensus donor splice site (ACTGAT/GTAAGA to ACTGAG/GTAAGA; / indicates the splice site). In the transcribed IVS2705 pre-mRNA, the presence of this new 5' splice site activates an acceptor splice site 126 nt upstream, resulting in incorrectly spliced b-globin mRNA containing a fragment of the intron (Fig. 1A). This fragment creates a premature stop codon resulting in a truncated b-globin polypeptide." Multiple functional studies support these predictions (Dobkin_1983, Spenc_1982, and Gorman_1998). The variant was absent in 30972 control chromosomes (gnomAD). The variant, c.316-146T>G, has been reported in the literature in individuals affected with Beta Thalassemia Intermedia. These data indicate that the variant may be associated with disease. A ClinVar submission (evaluation after 2014) from a clinical diagnostic laboratory classifies the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506214 SCV000603919 pathogenic not specified 2017-06-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985748 SCV001134226 pathogenic not provided 2019-05-10 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data are high quality. Found in at least one symptomatic patient. Low nucleotide conservation. Assessment of experimental evidence suggests this variant results in abnormal protein function. Moderate co-segregation with disease.
OMIM RCV000016714 SCV000036984 pathogenic Beta-plus-thalassemia 1983-03-01 no assertion criteria provided literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000029979 SCV001244412 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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.