ClinVar Genomic variation as it relates to human health

Variant summary: HBB c.-31C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 6.4e-05 in 250664 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in HBB causing Beta Thalassemia (6.4e-05 vs 0.011), allowing no conclusion about variant significance. c.-31C>T has been widely reported in the literature to co-occur in cis with other disease causing variants such as IVS-II-745C>G (c.316-106C>G) in individuals affected with Beta Thalassemia (example, Gonzalez-Redondo_1989, Lemsaddek_2003, Yavarian_2001, Galehdari_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Beta Thalassemia. Locus specific databases report this variant predominantly as benign. At least one publication reports experimental evidence evaluating an impact on expression of beta globin mRNA, however, does not allow convincing conclusions about the variant effect (example, Irenge_2002). The following publications have been ascertained in the context of this evaluation (PMID: 18976160, 20854120, 22737496, 2713503, 20113284, 12324499, 12827652, 19657842, 20704537, 15108284, 11300348). Six clinical diagnostic laboratories and a database (ITHANET) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without and classifed the variant as benign/likely benign (n=4) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign.

HBB: PP4, BP2, BP5

The HBB c.-31C>T variant, commonly referred to as 5’UTR+20, C>T, has been described in at least four studies in which it is found in cis with the same intronic variant, c.316-106C>G (commonly referred to as IVS-II-745 (C>G)). The c.-31C>T variant was found in a homozygous state in three individuals with a severe form of beta-thalassemia, in a compound heterozygous state in an additional three individuals with the same severe phenotype, and in a heterozygous state in six individuals, all with a milder phenotype. In all cases, the c.-31C>T variant was in cis with the intronic variant (Yavarian et al. 2001; Liaw et al. 2009; Ropero et al. 2013; Farashi et al. 2015). Sirdah et al. (2013) also reported the c.-31C>T variant in a compound heterozygous state in one individual with beta-thalassemia who did not carry the intronic variant. The c.-31C>T variant is reported at a frequency of 0.00014 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the c.-31C>T variant is classified as a variant of unknown significance for HBB-related disorders.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

The HBB c.-31C>T variant is located in the 5' untranslated region. This variant has also been described in the literature as 5' UTR+20(C>T) or +20(C>T) or 5’UTR-31(C>T) or C>T at nt +20 to the Cap site or β++20 (C>T). This variant has been frequently observed on the same allele (in cis) with the disease-causing variant c.316-106C>G (a.k.a. "IVS-II-745") in multiple individuals with beta thalassemia (Table 1, footnotes, Reported as C>T at nt position +20 to the Cap site, Gonzalez-Redondo et al. 1989. PubMed ID: 2713503; Reported as β++20 (C>T), Lemsaddek et al. 2003. PubMed ID: 12827652; Table 1, n 22, Reported as IVS-II-745 (C>G)+5’UTR+20(C>T), Galehdari et al. 2010. PubMed ID: 20854120; Table 1, Reported as +20(C>T), Ropero et al. 2013. PubMed ID: 23425204; Table 1 and 2, Reported as c.-31C>T, Carrocini et al. 2017. PubMed ID: 28366028). However, it has also been observed without the c.316-106C>G variant in a severely affected individual who was potentially compound heterozygous for c.-31C>T and a second pathogenic HBB variant, c.93-21G>A [a.k.a. "IVS-1-110 (G>A)"] (Tables 3 and 4, Reported as 5’UTR;+20(C>T), c.-31C>T, and 5’UTR-31(C>T), Sirdah et al. 2013. PubMed ID: 23321370). Additionally, an in vitro RT-PCR-based study reported a ~50% reduction in HBB mRNA expression for the c.-31C>T allele (without c.316-106C>G) relative to wild type (Table 1, Reported as +20C>T, Irenge et al. 2002. PubMed ID: 12324499). This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.