ClinVar Genomic variation as it relates to human health

The HBB c.92+2T>A variant (rs33956879), also known as IVS-I-2 T>A, is reported in the literature in multiple individuals affected with beta-thalassemia who carried a second pathogenic HBB variant (Bouhass 1990, Murru 1991, HbVar database). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. 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 c.92+2T>A: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=819&.cgifields=histD Bouhass R et al. A new mutation at IVS1 nt 2(T----A), in beta-thalassemia from Algeria. Blood. 1990 Sep 1;76(5):1054-5. Murru S et al. Molecular characterization of beta-thalassemia intermedia in patients of Italian descent and identification of three novel beta-thalassemia mutations. Blood. 1991 Mar 15;77(6):1342-7.

This variant disrupts a canonical splice-donor site and interferes with normal HBB mRNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). It is reported to be associated with beta(0) thalassemia in the published literature (PMID: 9163586 (1997), 2001456 (1991), 2393712 (1990)). Based on the available information, this variant is classified as pathogenic. Previous names for this pathogenic variant include IVS-I-2 (T>A).

This sequence change affects a donor splice site in intron 1 of the HBB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 38667). This variant is also known as IVS nt 2(T>A) or IVS-I-nt2 (T-A). Disruption of this splice site has been observed in individuals with beta thalassemia (PMID: 2001456, 2393712, 24986053, 28366028).

Variant summary: HBB c.92+2T>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251218 control chromosomes. c.92+2T>A has been reported in the literature in multiple individuals affected with hemoglobin disorders (Bilgen_2011, Hoppe_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.