Submissions for variant NM_000518.5(HBB):c.135del (p.Phe46fs)

dbSNP: rs80356820

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169145	SCV000220366	pathogenic	beta Thalassemia	2014-05-31	criteria provided, single submitter	literature only
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507725	SCV000601242	pathogenic	not provided	2021-10-14	criteria provided, single submitter	clinical testing	The HBB c.135del (p.Phe46Leufs*16) variant alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. This variant has been reported to be associated with beta(0)-thalassemia (PMIDs: 6292840 (1982), 1986379 (1991)). Previous names for this variant include Codon 44 (-C) and Frameshift 44 (-C). Based on the available information, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507725	SCV000603916	pathogenic	not provided	2024-07-05	criteria provided, single submitter	clinical testing	The HBB c.135delC; p.Phe46LeufsTer16 variant (also known as Codon 44 (-C) or Phe45fs when numbered from the mature protein, rs80356820, HbVar ID: 854) is described in the literature in the homozygous and trans-heterozygous state in individuals affected with beta (0) thalassemia (Jalilian 2017, HbVar and references therein). It has also been reported in the heterozygous state in individuals affected with mild microcytic anemia (De Angioletti 2013, Han 2016, HbVar and references therein). This variant is found on only four chromosomes (4/251414 alleles) in the Genome Aggregation Database and is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 15415). 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 De Angioletti M et al. South-Italy beta0-thalassemia: a novel deletion not removing the gamma-globin silencing element and with 3' breakpoint in a hsRTVL-H element, associated with beta0-thalassemia and high levels of HbF. Haematologica. 2013 98(8):e98-e100. PMID: 23812938. Han L et al. Molecular Epidemiological Survey of Glucose-6-Phosphate Dehydrogenase Deficiency and Thalassemia in Uygur and Kazak Ethnic Groups in Xinjiang, Northwest China. Hemoglobin. 2016 Jun;40(3):179-86. PMID: 26950205. Jalilian M et al. The Frequency of HBB Mutations Among beta-Thalassemia Patients in Hamadan Province, Iran. Hemoglobin. 2017 Jan;41(1):61-64. PMID: 28391758.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169145	SCV000697078	pathogenic	beta Thalassemia	2016-08-15	criteria provided, single submitter	clinical testing	Variant summary: The HBB c.135delC (p.Phe46Leufs) 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.143_146dupATCT (p.Thr51fs)). One in silico tool predicts a damaging outcome for this variant. This variant was found in 4/121382 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant has been reported in numerous BTHAL patients and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. The variant has been indicated to be a common BTHAL mutation in Middle Eastern individuals. Taken together, this variant is classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000507725	SCV001450174	pathogenic	not provided	2016-01-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000507725	SCV001578259	pathogenic	not provided	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe46Leufs*16) 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 (rs80356820, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with beta thalasemia (PMID: 1986379, 23812938, 28391758, 28670940). This variant is also known as Codon 44 (-C). ClinVar contains an entry for this variant (Variation ID: 15415). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000169145	SCV001810469	pathogenic	beta Thalassemia	2021-07-22	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001723571	SCV001950084	likely pathogenic	Dominant beta-thalassemia	2021-06-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005003363	SCV002815877	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	2024-05-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000507725	SCV003827037	pathogenic	not provided	2022-02-22	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000169145	SCV004848834	pathogenic	beta Thalassemia	2022-11-03	criteria provided, single submitter	clinical testing	The p.Phe46LeufsX16 variant in HBB has been reported in individuals affected with beta thalassemia (and in the heterozygous state in individuals affected with mild microcytic anemia) (selected references: De Angioletti 2013 PMID: 23812938, Han 2016 PMID: 26950205, Jalilian 2017 PMID: 28391758, https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=854). It has also been reported in ClinVar (Variation ID15415) and was absent from large population databases. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 46 and leads to a premature termination codon 16 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.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV004813042	SCV005438154	pathogenic	Malaria, susceptibility to	2024-12-17	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV004821260	SCV005442652	pathogenic	Beta-thalassemia HBB/LCRB	2023-06-22	criteria provided, single submitter	clinical testing	The frameshift variant c.135del p.Phe46LeufsTer16 in HBB gene has been observed in multiple individuals with beta thalasemia Hussain et. al., 2017; Jalilian et. al., 2017; Hassan et. al., 2015. This variant is also known as Codon 44 -C. The observed variant has allele frequency of 0.001% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic multiple submitters. This variant causes a frameshift starting with codon Phenylalanine 46, changes this amino acid to Leucine residue, and creates a premature Stop codon at position 16 of the new reading frame, denoted p.Phe46LeufsTer16. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HBB are known to be pathogenic Thein SL. 2013. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000016671	SCV000036941	pathogenic	Beta zero thalassemia	1982-09-25	no assertion criteria provided	literature only
GeneReviews	RCV000169145	SCV000040705	not provided	beta Thalassemia		no assertion provided	literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000169145	SCV001244551	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000169145	SCV002089221	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing