ClinVar Genomic variation as it relates to human health

Variant summary: The HBB c.114G>A (p.Trp38X) variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.118C>T/p.Gln40X, c.130G>T/p.Glu44X, etc). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 30964 control chromosomes. It has been reported in many BTHAL patients (both intermediate and major types) in both homozygous and comound heterozygous status. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/ likely pathogenic. Ithanet lists variant as ' Globin gene causative mutation' with relative frequencies of 6.3% in Jordan, 4.05% in Syria, 1.08% in Tunisia, 1% in Egypt, 0.3% in Czech Republic, 0.3% in Slovakia, 0.3% in Pakistan, and 0.3% in Spain. Taken together, this variant is classified as pathogenic.

The HBB c.114G>A; p.Trp38Ter variant (rs33974936), also known as Codon 37 (G->A), is reported in multiple individuals diagnosed with beta-thalassemia, and associated with beta-0 trait (Asadov 2013, Boehm 1986, Fernandes 2011, Gallano 1992, HbVar database and references therein). This variant is also reported as pathogenic in ClinVar (Variation ID: 15405). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Link to HbVar database for Codon 37 (G->A): http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=841 Asadov C et al. Identification of two rare B-globin gene mutations in a patient with B-thalassemia intermedia from Azerbaijan. Hemoglobin. 2013; 37(3):291-6. Boehm C et al. Use of oligonucleotide hybridization in the characterization of a beta zero-thalassemia gene (beta 37 TGG----TGA) in a Saudi Arabian family. Blood. 1986; 67(4):1185-8. Fernandes A et al. Molecular analysis of beta-thalassemia patients: first identification of mutations HBB:c.93-2A>G and HBB:c.114G>A in Brazil. Hemoglobin. 2011; 35(4):358-66. Gallano P et al. High prevalence of the beta-thalassaemia nonsense 37 mutation in Catalonians from the Ebro delta. Br J Haematol. 1992; 81(1):126-7.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported as pathogenic in a well-curated hemoglobin database but additional evidence is not available (Giardine et al., 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 22385009, 3006832, 23510507, 21797703)

The HBB c.114G>A (p.Trp38*) variant (also known as Codon 37 (G>A) and W37X) causes the premature termination of beta-globin (HBB) protein synthesis and is associated with beta(0)-thalassemia (PMID: 3006832 (1986), 15008262 (2004), 18096416 (2008), 23321370 (2013), 23510507 (2013)).

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 15405). This premature translational stop signal has been observed in individual(s) with beta thalassemia (PMID: 3006832, 28670940). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp38*) in the HBB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309).