Submissions for variant NM_000518.5(HBB):c.52A>T (p.Lys18Ter)

gnomAD frequency: 0.00002  dbSNP: rs33986703

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507505	SCV000603897	pathogenic	not provided	2023-11-16	criteria provided, single submitter	clinical testing	The HBB c.52A>T; p.Lys18Ter variant (also known as Lys17Ter when numbered from the mature protein or as Codon 17 (A>T), rs33986703, HbVar ID: 800) has been reported in multiple individuals with beta thalassemia, and is considered a beta(0) thalassemia variant (HbVar database and references therein). This variant introduces a premature termination codon, so it 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: https://globin.bx.psu.edu/hbvar/hbvar.html
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020337	SCV000697138	pathogenic	beta Thalassemia	2016-07-28	criteria provided, single submitter	clinical testing	Variant summary: The HBB c.52A>T (p.Lys18X) 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.85dupC/p.Leu29fsX16). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/121842 control chromosomes at a frequency of 0.0000164, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant has been reported in many BTHAL patients (mostly East Asian) both homozygously and in compound heterozygosity with other pathogenic variant. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
GeneDx	RCV000507505	SCV000890267	pathogenic	not provided	2022-09-28	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: 21389146, 88735, 26029792, 30275481, 34426522, 8161731, 2143120, 26715484, 22975760, 29669226, 29695942)
Fulgent Genetics, Fulgent Genetics	RCV000763255	SCV000893892	pathogenic	Dominant beta-thalassemia; Fetal hemoglobin quantitative trait locus 1; Heinz body anemia; Hb SS disease; alpha Thalassemia; Malaria, susceptibility to; beta Thalassemia; Methemoglobinemia, beta-globin type; Erythrocytosis, familial, 6	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000507505	SCV000945919	pathogenic	not provided	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys18*) 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 present in population databases (rs33986703, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with beta thalassemia (PMID: 88735, 24857915, 26029792). It is commonly reported in individuals of Asian ancestry (PMID: 20412082, 25089872, 25849334, 29695942). This variant is also known as "Codon 17 (A->T)" and "AAG(Lys)->TAG(stop codon) beta0". ClinVar contains an entry for this variant (Variation ID: 15401). 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.
Baylor Genetics	RCV001004355	SCV001163291	pathogenic	Hb SS disease		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000020337	SCV001193814	pathogenic	beta Thalassemia	2019-12-19	criteria provided, single submitter	clinical testing	NM_000518.4(HBB):c.52A>T(K18*) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy; it is associated with beta thalassemia and is classified as a beta-zero variant. Sources cited for classification include the following: PMID 22335963. Classification of NM_000518.4(HBB):c.52A>T(K18*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000507505	SCV001449941	pathogenic	not provided	2018-07-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000020337	SCV001520750	pathogenic	beta Thalassemia	2020-07-24	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
MGZ Medical Genetics Center	RCV002288498	SCV002580829	pathogenic	Beta-thalassemia HBB/LCRB	2022-03-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507505	SCV002774345	pathogenic	not provided	2021-08-30	criteria provided, single submitter	clinical testing	The nonsense variant causes the premature termination of HBB protein synthesis. In addition, it has been reported to be associated with beta(0)-thalassemia in the published literature (PMID: 29695942 (2018), 9101288 (1997), 2606476 (1989) and 88735 (1979)). Based on the available information, this variant is classified as pathogenic.
Revvity Omics, Revvity	RCV000507505	SCV003822728	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing
OMIM	RCV000016655	SCV000036924	pathogenic	Beta zero thalassemia	2000-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000020337	SCV000040713	not provided	beta Thalassemia		no assertion provided	literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000020337	SCV001244648	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000020337	SCV002091601	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing