Understanding the functional consequences of a variant

Now that we know that rs334 is missense in HBB, and that it is associated with sickle cell anaemia we can start to probe the protein structure to understand the molecular mechanisms underlying this association.

Searching Uniprot for variant identifiers

As we saw in the first case study, you can explore proteins and their variants using UniProt. As with genes or proteins you can search UniProt using the variant identifier (rs334).

There is one protein associated with this variant: human hemoglobin subunit B. By looking at the Pathology and Biotech section for this protein we can see that the variant associated with sickle cell anaemia is p.Glu7Val and causes a change from a charged amino acid to a hydrophobic aliphatic amino acid.  This is annotated as E -> V at position 7 (Figure 9).

Figure 9 The UniProt Pathology and Biotech section for human hemoglobin subunit B shows which variants are associated with sickle cell anaemia (view in UniProt).

Using Uniprot’s feature viewer

If we take a look at the feature viewer for this protein you can see that this variant does not occur within the region of the essential heme binding residues, but does occur in an alpha-helix within a small cluster of charged residues (Figure 10).

Figure 10 The UniProt feature viewer for human haemoglobin subunit B (view in UniProt for full annoations).