Submissions for variant NM_000518.5(HBB):c.17_18del (p.Pro6fs)

dbSNP: rs34889882

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506399	SCV000601252	pathogenic	not provided	2023-05-22	criteria provided, single submitter	clinical testing	The HBB c.17_18del (p.Pro6Argfs*17) variant (also known as CD5 (-CT)) alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. In the published literature, this variant has been reported in the compound heterozygous and homozygous state in individuals with beta-thalassemia major and intermedia (PMIDs: 33491330 (2021), 27263053 (2016), 25617386 (2015), 2606727 (1989)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586913	SCV000697089	pathogenic	beta Thalassemia	2017-06-06	criteria provided, single submitter	clinical testing	Variant summary: The HBB c.17_18delCT is a frame-shift variant resulting in termination of translation at codon 23, which is predicted to cause either a truncated or absent HBB protein through non-sense mediated decay which is a commonly known mechanism for BTHAL. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Leu29fs). This variant is found in 1/121340 control chromosomes from ExAC at a frequency of 0.0000082, which does not exceed the maximal expected frequency of a pathogenic allele (0.0111803) in this gene. This variant has been commonly identified in beta-thalassemia patients in both compound heterozygous and homozygous states. It is also reported as one of the common mutations in Middle Eastern countries (Lahiry_2008). Taken together, this variant has been classified as a disease variant/pathogenic.
Counsyl	RCV000586913	SCV000799824	pathogenic	beta Thalassemia	2018-05-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506399	SCV001160085	pathogenic	not provided	2023-11-15	criteria provided, single submitter	clinical testing	The HBB c.17_18delCT; p.Pro6ArgfsTer17 variant (rs34889882, HbVarID: 783), also known as Codon 5 (-CT) or Pro5fs when numbered from the mature protein, has been reported in the literature in an individual with beta(0) thalassemia (Kollia 1989, HbVar database and references therein). This variant is reported as pathogenic in ClinVar (Variation ID: 15422). It is found in the general population with an overall allele frequency of 0.004% (11/251156 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 2 nucleotides, 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 Kollia et al. Frameshift codon 5 (Fsc-5 (-CT)) thalassemia; a novel mutation detected in a Greek patient. Hemoglobin. 1989;13(6):597-604. PMID: 2606727.
Baylor Genetics	RCV001004360	SCV001163298	pathogenic	Hb SS disease		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000506399	SCV001215748	pathogenic	not provided	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro6Argfs*17) 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 (rs34889882, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with beta thalassemia (PMID: 2606727). This variant is also known as Pro5fs and FSC-5(-CT). ClinVar contains an entry for this variant (Variation ID: 15422). 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	RCV000506399	SCV001450168	pathogenic	not provided	2016-01-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000506399	SCV001500949	pathogenic	not provided	2021-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005003366	SCV001752822	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	2024-04-27	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000586913	SCV001810474	pathogenic	beta Thalassemia	2021-07-22	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000586913	SCV004847531	pathogenic	beta Thalassemia	2022-11-03	criteria provided, single submitter	clinical testing	The p.Pro6ArgfsX17 variant in HBB has been reported in several individuals with beta thalassemia and is one of the common pathogenic variants in Middle Eastern countries ( selected references Kollia 1989 PMID: 2606727, Vetter 1997 PMID: 9163586, Murad 2021 PMID: 33491330). It has also been reported in ClinVar (Variation ID 15422) and was identified in 6/4834 South Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 6 and leads to a premature termination codon 17 amino acids downstream. This alteration is then 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.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV004566747	SCV005051815	pathogenic	Beta-thalassemia HBB/LCRB	2024-02-01	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000506399	SCV005090883	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV005000984	SCV005627566	pathogenic	Dominant beta-thalassemia	2024-12-27	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4,PM2_SUP
OMIM	RCV000016678	SCV000036948	pathogenic	Beta zero thalassemia	1989-01-01	no assertion criteria provided	literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000586913	SCV001244626	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000586913	SCV002091615	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541006	SCV004793003	pathogenic	HBB-related disorder	2024-02-11	no assertion criteria provided	clinical testing	The HBB c.17_18delCT variant is predicted to result in a frameshift and premature protein termination (p.Pro6Argfs*17). This variant is also known as Codon 5 [-CT], FSC-5(-CT), or CD 5 -CT in the literature. This variant was reported in the homozygous and compound heterozygous states to be causative for autosomal recessive beta-thalassemia (Kollia et al. 1989. PubMed ID: 2606727; Elmezayen et al. 2015. PubMed ID: 25617386; Murad et al. 2021. PubMed ID: 33491330). This variant is reported in 0.036% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in HBB are expected to be pathogenic. This variant is interpreted as pathogenic.
MOLECULAR BIOLOGY AND HUMAN GENETICS DIVISION, THE UNIVERSITY OF BURDWAN	RCV004566747	SCV005186160	pathogenic	Beta-thalassemia HBB/LCRB	2024-05-07	no assertion criteria provided	clinical testing	The HBB c.17_18delCT (NP_000509.1:p.Pro6fs ) is a frame-shift variant, which is also a beta 0 mutation. When this variant present with other pathogenic HBB mutation leads to severe type of thalassemia. Patients needing blood transfusion, often presented with hepatosplenomegaly, Iron overload. The frequency of the variant among thalassemia patient in Eastern India is 0.19 % as per our multicentric project - A Genetic Diagnostic Algorithm Based Study for Thalassemia in Northern and Eastern Indian Populations, Funded by Dept. of Biotechnology , Govt of India [Project No. BT/PR26461/MED/12/821/2018]