ClinVar Genomic variation as it relates to human health

Variant summary: HBB c.382C>T (p.Gln128X, also reported as p.Glu127X) is located in exon 3 (i.e. in the last exon) of the HBB gene. The current variant results in a premature termination codon that is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a C-terminal truncation, removing a part of the 147 amino acid long protein. A truncation downstream of this position has been classified as pathogenic for dominant B-THAL by our laboratory. The variant allele was found at a frequency of 4e-06 in 251276 control chromosomes (gnomAD). c.382C>T has been reported in the literature in multiple individuals affected with considerable variation in phenotype (even within the same famlily), ranging from mild, clinically asymptomatic anemia to severe hemolytic anemia with splenomegaly (e.g. Hall_1991, Van Weel_1999, Prehu_2005), where occasionally the presence of Heinz bodies was also noted. These data indicate that the variant is likely associated with disease. A publication reported experimental evidence and demonstrated that substantial amounts of mutant beta-mRNA were present in individuals carrying the variant, thus demonstrating that the variant does not result in nonsense mediated decay (NMD), suggesting that a truncated protein product can be produced, which might also explain the presence of the occasionally reported Heinz bodies (Hall_1994). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic for dominant B-THAL.

The HBB c.382C>T (p.Gln128*) variant creates a premature stop codon in the last exon of the beta-globin gene. An RNA study indicates the mutant mRNA transcript is not degraded by nonsense-mediated decay, and is predicted to result in the production of a truncated protein lacking the terminal 20 amino acids of the beta-globin chain (PMID: 8161774 (1994)). This variant is associated with dominant beta-thalassemia in which heterozygous carriers present with varying phenotype, ranging from clinically asymptomatic anemia to thalassemia intermedia (PMIDs: 9450794 (1998), 8161774 (1994), 1958498 (1991)). In addition, this variant has been reported as a de novo variant in a heterozygous individual with microcytic hypochromic hemolytic anemia and splenomegaly (PMID: 10569730 (1999)). Previous names for this variant include Codon 127 C>T. Based on the available information, this variant is classified as pathogenic.