ClinVar Genomic variation as it relates to human health

Observed with a pathogenic variant in a patient with beta-thalassemia in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Luo et al., 2005; Gupta et al., 2023); Reported as a common variant among individuals of South Indian background (Sinha et al., 2009; Baysham et al., 2012); Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as IVS-II-837 (T>G) using alternate nomenclature; This variant is associated with the following publications: (PMID: 30489691, 31766235, 1772786, 32412692, 23651435, 18294253, 22734501, 12709369, 15278762, 19254853, 23590658, 20437613, 19205975, 35620315, Gupta[article]2023, 33829933, 21119755, 15933066, 20230396)

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant is associated with beta(+)-thalassemia or beta(0)-thalassemia (PMID: 1772786 (1991), 18294253 (2008), 19205975 (2009), 22734501 (2012)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on HBB mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Based on the available information, this variant is classified as pathogenic.

The HBB c.316-14T>G variant (rs35703285, HbVar ID: 895), also known as IVS-II-837T>G, has been reported in the heterozygous state in individuals affected with microcytosis and hypochromia and is associated with an intermediate beta thalassemia phenotype when in combination with a beta(0) HBB variant on the opposite chromosome (Link to HbVar, Luo 2005, Nadkarni 2009, Sinha 2009, Varawalla 1991). It is reported in ClinVar (Variation ID: 36313) and absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site. Based on available information, this variant is considered pathogenic. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/hbvar.html Luo H et al. Patients with thalassemia in the United States. Blood. 2005 Jun 15;105(12):4896-7. PMID: 15933066. Nadkarni A et al. Hematological and molecular analysis of novel and rare beta-thalassemia mutations in the Indian population. Hemoglobin. 2009;33(1):59-65. PMID: 19205975. Sinha S et al. Profiling B-thalassaemia mutations in India at state and regional levels: implications for genetic education, screening and counselling programmes. Hugo J. 2009 Dec;3(1-4):51-62. PMID: 21119755 Varawalla N et al. Rare beta-thalassaemia mutations in Asian indians. Br J Haematol. 1991 Dec;79(4):640-4. PMID: 1772786.

Converted during submission to Pathogenic.

This sequence change falls in intron 2 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with beta thalasemia (PMID: 15933066, 19205975, 22734501, 23590658). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS II:837 T>G. ClinVar contains an entry for this variant (Variation ID: 36313). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.