ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.114G>A (p.Trp38Ter) (rs33974936)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169502 SCV000220964 likely pathogenic beta Thalassemia 2014-12-16 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506223 SCV000601235 pathogenic not provided 2017-06-30 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000999750 SCV000883989 pathogenic not specified 2019-06-28 criteria provided, single submitter clinical testing 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): 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.
Integrated Genetics/Laboratory Corporation of America RCV000781456 SCV000919492 pathogenic Hemoglobinopathy 2017-12-18 criteria provided, single submitter clinical testing 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.
OMIM RCV000016659 SCV000036928 pathogenic beta^0^ Thalassemia 1986-04-01 no assertion criteria provided literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000169502 SCV001244538 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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