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

dbSNP: rs63750783

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508601	SCV000603905	pathogenic	not provided	2023-10-13	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, HbVar ID: 791) has been reported in individuals with beta(0) 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: https://globin.bx.psu.edu/hbvar/menu.html Kazazian HH Jr et al. Molecular characterization of seven beta-thalassemia mutations in Asian Indians. EMBO J. 1984; 3(3):593-6. PMID: 6714226. 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. PMID: 21389146.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508601	SCV000605842	pathogenic	not provided	2017-06-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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 Genetics, 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	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp16*) in the HBB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 132 amino acid(s) of the HBB protein. This variant is present in population databases (rs63750783, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with beta thalassemia and has been reported as a prevalent disease-associated variant in several populations (PMID: 1581247, 6714226, 7668221, 18294253, 20395516, 27263053, 27828729). This variant is also known as "Codon 15 (TGG->TGA)". ClinVar contains an entry for this variant (Variation ID: 15403). 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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000508601	SCV001450347	pathogenic	not provided	2016-11-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000576738	SCV001810476	pathogenic	beta Thalassemia	2021-07-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000508601	SCV003805330	pathogenic	not provided	2023-02-17	criteria provided, single submitter	clinical testing	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; This variant is associated with the following publications: (PMID: 22975760, 30200837, 29669226, 7668221, 6714226, 28635337, 21389146, 8091935, 27263053)
Neuberg Centre For Genomic Medicine, NCGM	RCV003985073	SCV004801421	pathogenic	Beta-thalassemia HBB/LCRB		criteria provided, single submitter	clinical testing	The stop gain c.47G>A (p.Trp16Ter) variant in HBB gene has been reported previously in both homozygous and compound heterozygous state in mulitple individuals affected with beta thalassemia, and is also one of the most common HBB variant causing beta thalassemia (Yasmeen et al. 2016; Panja et al. 2017). The p.Trp16Ter variant is reported with an allele frequency of 0.009% in the gnomAD exomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The nucleotide change c.47G>A in HBB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant in the HBB gene, the molecular diagnosis is not confirmed.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000576738	SCV004847534	pathogenic	beta Thalassemia	2022-11-03	criteria provided, single submitter	clinical testing	The p.Trp16X variant (also known as Trp15X) has been reported in numerous individuals with beta thalassemia (selected references Kazazian 1984 PMID: 6714226, HbVar database: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=791 ). It has been reported in ClinVar (Variation ID 15403) and was identified in 4/4834 South Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 16, which is predicted to lead to a truncated or absent protein. Loss of function of the HBB gene is an established disease mechanism in autosomal recessive beta thalassemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PM2_Supporting, PVS1, PM3_Strong.
OMIM	RCV000016657	SCV000036926	pathogenic	Beta zero 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
Natera, Inc.	RCV000576738	SCV002091604	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing