Submissions for variant NM_000518.5(HBB):c.48G>A (p.Trp16Ter)

gnomAD frequency: 0.00001  dbSNP: rs34716011

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508624	SCV000605843	pathogenic	not provided	2020-12-08	criteria provided, single submitter	clinical testing	The HBB c.48G>A (p.Trp16*) pathogenic variant (also known as CD 15 (G>A), Trp15X) causes the premature termination of HBB protein synthesis. This variant has been reported to be associated with beta(0)-thalassemia (PMIDs: 22875618 (2013), 19488752 (2009)). Individuals homozygous for this variant present with severe, transfusion-dependent anemia (PMID: 1581247 (1992)).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589075	SCV000697136	pathogenic	beta Thalassemia	2017-02-13	criteria provided, single submitter	clinical testing	Variant summary: The HBB c.48G>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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Lys18fsX2, p.Lys18X, p.Trp38fsX24). One in silico tool predicts a damaging outcome for this variant. The variant has been reported in numerous affected individuals in the literature and is absent in 121364 control chromosomes. In addition, a different variant (c.47G>A) leading to the same amino acid change has been classified as pathogenic, further supporting the pathogenic role of the variant of interest. Taken together, this variant is classified as pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000589075	SCV000746342	pathogenic	beta Thalassemia	2017-12-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000508624	SCV001589194	pathogenic	not provided	2024-02-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp16*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with beta thalassemia (PMID: 7668221, 19488752, 27263053). This variant is also known as Codon 15 (TGG>TGA). ClinVar contains an entry for this variant (Variation ID: 38646). 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.
Genome-Nilou Lab	RCV000589075	SCV001810467	pathogenic	beta Thalassemia	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000508624	SCV002024966	pathogenic	not provided	2019-08-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508624	SCV002048033	pathogenic	not provided	2021-06-07	criteria provided, single submitter	clinical testing	The Codon 15 (G->A); TGG ->TGA variant (HBB c.48G>A; p.Trp16Ter, also known as Trp15Ter when numbered from the mature protein, rs34716011) is reported in individuals with beta thalassemia (HbVar database and references therein). This variant is also reported in ClinVar (Variation ID: 38646). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, another variant at this codon (c.47G>A, p.Trp16Ter) has been reported in individuals with beta thalassemia and is considered pathogenic (HbVar 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 -> TGA: https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=793&.cgifields=histD 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 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 May;17(5):843-54. PMID: 21389146.
GeneDx	RCV000508624	SCV004036834	pathogenic	not provided	2023-09-17	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21389146, 2298457, 19488752, 23915319, 22875618, 35023007, 36074711, 35046417, 33935034, 30002798, 25341880, 6714226, 7668221, 27263053)
Fulgent Genetics, Fulgent Genetics	RCV005049397	SCV005684723	pathogenic	Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; Malaria, susceptibility to; METHEMOGLOBINEMIA, BETA TYPE; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB	2024-04-11	criteria provided, single submitter	clinical testing
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000589075	SCV001244643	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000589075	SCV002091602	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing