ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.47G>A (p.Trp16Ter) (rs63750783)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999920 SCV000603905 pathogenic not specified 2018-08-17 criteria provided, single submitter clinical testing The HBB c.47G>A; p.Trp16Ter variant (also known as Trp15Ter when numbered from the mature protein or as Codon 15 (G->A); TGG->TAG, rs63750783) has been reported in individuals with beta thalassemia (Kazazian 1984, HbVar database and references therein). This variant is found in the general population with an overall allele frequency of 0.009% (22/251244 alleles) in the Genome Aggregation Database. This variant introduces a premature termination codon, but the mRNA is resistant to nonsense-mediated decay (Neu-Yilik 2011); thus it is predicted to result in a truncated protein. Based on available information, this variant is considered to be pathogenic. REFERENCES Link to HbVar database for Codon 15 (G->A); TGG -> TAG: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=791 Kazazian HH Jr et al. Molecular characterization of seven beta-thalassemia mutations in Asian Indians. EMBO J. 1984; 3(3):593-6. Neu-Yilik G et al. Mechanism of escape from nonsense-mediated mRNA decay of human beta-globin transcripts with nonsense mutations in the first exon. RNA. 2011; 17(5):843-54.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508601 SCV000605842 pathogenic not provided 2017-06-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000576738 SCV000697135 pathogenic beta Thalassemia 2016-05-12 criteria provided, single submitter clinical testing Variant summary: The HBB c.47G>A (p.Trp16X) 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. Variant c.48G>A that gives the same codon change has been classified as pathogenic by our laboratory. One in silico tool predicts a damaging outcome for this variant. This variant was found in 14/121364 control chromosomes at a frequency of 0.0001154, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant has been reported in numerous beta thalassemia patients and is considered as a common disease variant. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics RCV001004356 SCV001163292 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000576738 SCV001193800 pathogenic beta Thalassemia 2019-12-16 criteria provided, single submitter clinical testing NM_000518.4(HBB):c.47G>A(W16*) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy and is associated with beta thalassemia. Sources cited for classification include the following: PMID 21389146, 15278762, 18294253 and 21389146. Classification of NM_000518.4(HBB):c.47G>A(W16*) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Invitae RCV000508601 SCV001217538 pathogenic not provided 2019-12-19 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the HBB gene (p.Trp16*). While it is expected to result in an absent or disrupted protein product, an alternate in-frame methionine (p.Met56, also known as p.Met55) downstream of the initiator codon could potentially rescue the translation initiation (PMID: 21389146). This variant is present in population databases (rs63750783, ExAC 0.08%). This variant has been observed in numerous individuals and families affected with beta thalassemia and has been reported as a prevalent disease-associated variant in several populations (PMID: 6714226, 7668221, 27828729, 27263053, 1581247, 20395516, 18294253). This variant is also known as "Codon 15 (TGG->TGA)" in the literature. ClinVar contains an entry for this variant (Variation ID: 15403). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000016657 SCV000036926 pathogenic beta^0^ Thalassemia 1992-04-01 no assertion criteria provided literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000576738 SCV001244583 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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