ClinVar Genomic variation as it relates to human health

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.

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.

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.

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.

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.