ClinVar

Description

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.