VUS Example: AA 3
A classic example is the Valine to Methionine change at a specific position (e.g., AA 3, a placeholder for an actual VUS) which is currently classified as a VUS in ClinVar, with no definitive insights available from standard population data.
This specific valine-to-methionine change exhibits profound evolutionary recurrence:
- Shared Ancestry: It is shared across 15 primate genera.
- Deep Time Conservation: It has existed in multiple primate species for over 30 million years (MY).
- Human Recurrence: Crucially, this variant recurs in human populations.
The deep evolutionary history and persistence of this specific change provide strong evidence suggesting it is functionally tolerated and likely benign, despite the initial VUS classification.
The MC1R Gene and Human Pigmentation
MC1R is an intronless gene that encodes the receptor protein for melanocyte-stimulating hormone (MSH).
- Structure and Function: The encoded protein is a seven-pass transmembrane G protein-coupled receptor that controls melanogenesis (pigment production).
- Clinical Significance: This receptor is a major determinant of sun sensitivity and serves as a significant genetic risk factor for both melanoma and non-melanoma skin cancer.
- Variation: Over 30 variant alleles have been identified that correlate with skin and hair color, highlighting the gene's essential role in normal human pigment variation. [provided by RefSeq, Jul 2008]
MC1R is vitally important for human pigmentation, offering protection against harmful UV radiation. However, its small size and complexity make it intractable for understanding skin cancer treatment responses.
- Gene Size and VUS Load: The gene is small, containing only a single coding region of 954 nucleotides, encoding 317 amino acids. Of these 317 residues, 204 amino acid positions (64%) are associated with Variants of Uncertain Significance (VUS) in human populations.
CodeXome's Impact on MC1R VUS
CodeXome leverages evolutionary data to reclassify VUS.
- Reclassification Success: CodeXome recodes 48 VUS in MC1R (representing 23.5% of the total number of ClinVar VUS for this gene) to 'Likely Benign' status.
- Structural Independence: The MC1R protein loops from the extracellular to the cytoplasmic space, traversing transmembrane regions seven times. The VUS are not confined to specific structural features, and CodeXome successfully converts VUS to 'Likely Benign' across all protein regions (extracellular, transmembrane, and cytoplasmic).
Predictive Power of Evolutionary Data
Sites like position 219 (another representative VUS) demonstrate the robust capabilities of the predictive scoring system, particularly the Deep Time Ancestry score, which is the second tool of the AI/ML approach.
- Predictive Score Example: The predictive score can re-classify variants even in the absence of sufficient gnomAD (population frequency) data, illustrating the power of gene evolution to provide critical information regarding a variant's potential functional impact. Evolutionary recurrence and conservation patterns offer a deep historical context for variant tolerance that is often missing from contemporary population studies.
