Submissions for variant NM_000518.5(HBB):c.251del (p.Gly84fs)

dbSNP: rs193922555

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507807	SCV000601262	pathogenic	not provided	2022-01-12	criteria provided, single submitter	clinical testing	The HBB c.251del (p.Gly84Alafs*6) variant (also known as 250delG and 82/83 (-G)) alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. This variant is associated with beta(0)-thalassemia (PMIDs: 28670940 (2017), 24719849 (2014), 1740317 (1992),1517107 (1992), 2525253 (1989)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169623	SCV000697101	pathogenic	beta Thalassemia	2017-05-24	criteria provided, single submitter	clinical testing	Variant summary: The HBB c.251delG (p.Gly84Alafs) 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.287dupA, p.Leu97fs). The variant of interest has not been found in a large and broad control population from ExAC in 121390 control chromosomes. This variant was reported in patients with beta thalassemia in a homozygous state as well compound heterozygotes with other pathogenic variants, including evidence of cosegregation with disease (El-Kalla_1997, Rahimi_2010, Al-Allawi_2014, and Ulasli_2015). In an Iraqi study that included 74 beta thalassemia patients, it was found in nine patients and was the third most common mutation (Al-Allawi_2014). In another Iranian study that included 185 beta thalassemia patients, its allele frequency was 1.08% (Rahimi_2010). Available data including clinical and biochemical picture of heterozygous carriers supports that this variant causes transfusion-dependent thalassemia in a homozygous state or in a compound heterozygous state with another severe (beta0) variant. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae	RCV000507807	SCV001374567	pathogenic	not provided	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly84Alafs*6) 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: 2525253, 24719849, 27756326, 28670940). This variant is also known as 250delG and 82/83 (-G). ClinVar contains an entry for this variant (Variation ID: 36306). For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000507807	SCV001450117	pathogenic	not provided	2014-11-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507807	SCV002048499	pathogenic	not provided	2023-01-09	criteria provided, single submitter	clinical testing	The HBB c.251delG; p.Gly84AlafsTer6variant (also known as Codons 82/83 (-G), rs193922555, HbVar ID: 875) is reported in the literature in multiple individuals with beta(0) thalassemia in the homozygous or compound heterozygous state (see HbVar and references therein, Al-Allawi 2014, Hancer 2020, Ulasli 2015). This variant is also reported in ClinVar (Variation ID: 36306), but is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, 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 database: https://globin.bx.psu.edu/hbvar/menu.html Al-Allawi NA et al. Beta-thalassemia intermedia in Northern Iraq: a single center experience. Biomed Res Int. 2014;2014:262853. PMID: 24719849. Hançer VS et al. Two Rare Pathogenic HBB Variants in a Patient with Beta-Thalassemia Intermedia. Turk J Haematol. 2020 May 6;37(2):135-136. PMID: 32069775. Ulasli M et al. Novel ?eta-Thalassemia Mutation in Turkish Children. Indian J Hematol Blood Transfus. 2015 Jun;31(2):218-22. PMID: 25825561.
MGZ Medical Genetics Center	RCV002288523	SCV002581782	pathogenic	Beta-thalassemia HBB/LCRB	2022-06-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000169623	SCV000221151	pathogenic	beta Thalassemia	2015-11-16	no assertion criteria provided	clinical testing
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000169623	SCV001244555	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000169623	SCV002089206	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing