ClinVar

Description

Variant summary: HBB c.1A>G alters the initiation codon (i.e. ATG coding for methionine to a triplet GTG coding for valine, so the predicted protein level name would be p.Met1Val), and it is expected that the next available, downstream ATG codon will be used as a translational start site. However, as it is out of frame (located at codons 21-22), this would result in a frameshift followed by an early termination (at the next in-frame stop codon 118 nucleotides downstream), likely leading to a missing/non-functional protein product (Hattori 1991). Two of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 245874 control chromosomes. The c.1A>G variant has been reported in the literature in multiple individuals in the heterozygous state causing Beta Thalassemia Minor (e.g. Hattori 1991, Huisman 1997, Ohba 1997, Perea 2004, Liu 2011), however it is expected that in homozygosity and/or compound heterozygosity with a severe variant, this variant is likely to cause the BTHAL MJR phenotype. Other changes affecting the initiation codon (such as: c.2T>G (p.Met1Arg), c.2T>C (p.Met1Thr), c.3G>A (p.Met1Ile)) have also been found in HBB patients (source: HGMD). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.