Studies on the functional consequences of variants

The majority of genetic variants that we observe are tolerated by an organism but some variants can change the function of a gene’s product. Functional genetic variation studies aim to understand the molecular mechanisms and pathways that link genotype to phenotype.

In human genetics this is an important step in translating genotype data for use in the clinic¹¹.

Simple variants that alter the translated protein sequence, such as, missense, splice site variant, stop gained, stop lost variants, can cause functional consequences by:

1. Altering ligand and/or co-factor binding sites
2. Alter the natural protein structure by:
   • a. Removing or adding additional cysteine reduces that can alter disulfide bond patterns
   • b. Alter normal formation of secondary structure elements or their interaction (sickle cell anaemia is an example of this)
   • c. Disrupt the normal interactions between proteins’ tertiary protein complexes or other cellular components
3. Remove or add post-translational modification sites

The functional consequences can be interpreted using prediction tools such as Ensembl’s Variant Effect Predictor (VEP). Known or predicted functional consequences for variants of a specific protein are summarised in UniProt.

Functional consequences due to structural variants are usually defined by the physiological phenotypes observed.  These can be complex descriptions which are described using general phenotypic traits rather than specific biochemical effects caused by the variant. Clinical functional consequences are represented by a simple controlled vocabulary that defines the relative pathogenicity of a variant (Table 2). Ensembl use a standard set of clinical significance terms are defined by the ACMG/AMP ¹².

Table 2 Controlled vocabulary terms used to describe clinical functional consequences of a variant

We will learn more about exploring the functional consequences for variants in specific proteins in the case studies of Human genetic variation: Exploring publicly available data.