Submissions for variant NM_000518.5(HBB):c.203_204del (p.Val68fs)

dbSNP: rs34282684

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508401	SCV000601257	pathogenic	not provided	2021-08-12	criteria provided, single submitter	clinical testing	The HBB c.203_204del (p.Val68Alafs*5) variant 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 (PMID: 8257991 (1993)). Previous names for this variant include Codon 67 (-TG). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590298	SCV000697091	pathogenic	beta Thalassemia	2023-08-21	criteria provided, single submitter	clinical testing	Variant summary: HBB c.203_204delTG (p.Val68AlafsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251412 control chromosomes (gnomAD). c.203_204delTG has been reported in the literature in at least one individual affected with Beta Thalassemia (e.g. Eng_1993). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=5) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000508401	SCV000949031	pathogenic	not provided	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val68Alafs*5) 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: 8257991). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 36303). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508401	SCV001158004	pathogenic	not provided	2023-11-15	criteria provided, single submitter	clinical testing	The HBB c.203_204delTG; p.Val68AlafsTer5 variant (rs34282684, HbVar ID: 868), also known as Codon 67 (-TG), is reported in the literature in an individual with beta-thalassemia major in trans to a whole-gene HBB deletion (Eng 1993). The c.203_204delTG variant was also observed in heterozygous relatives with hematological profiles consistent with beta-thalassemia minor (Eng 1993). This variant is reported in ClinVar (Variation ID: 36303) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting two 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 Eng B et al. Identification of two novel beta zero-thalassemia mutations in a Filipino family: frameshift codon 67 (-TG) and a beta-globin gene deletion. Hum Mutat. 1993;2(5):375-9. PMID: 8257991
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000508401	SCV001449703	pathogenic	not provided	2018-01-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496454	SCV002813817	pathogenic	Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; alpha Thalassemia; Malaria, susceptibility to; METHEMOGLOBINEMIA, BETA TYPE; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB	2021-11-24	criteria provided, single submitter	clinical testing
Counsyl	RCV000590298	SCV001132414	likely pathogenic	beta Thalassemia	2015-11-16	no assertion criteria provided	clinical testing