# The disruptive influence of the Ala218Val variant on the ENG protein

## TL;DR

This study examines how a specific genetic variant in the ENG gene disrupts artery development and causes bleeding in a disease called Hereditary Hemorrhagic Telangiectasia.

## Contribution

The study provides computational evidence that the Ala218Val variant in the ENG protein is likely pathogenic.

## Key findings

- The Ala218Val variant is located at a highly conserved and buried residue in the ENG protein.
- Molecular dynamics simulations show the variant causes structural movement differences compared to the wild type.
- The variant is predicted to be likely pathogenic based on computational and conservation analyses.

## Abstract

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease that interferes with the formation of arteries. The
ENG
gene encodes for the protein endoglin which is used to properly develop and remodel arteries. The removal of endoglin forms telangiectasias that cause bleeding from the nose and vital organs. This study investigates the impact of one of the many variants of uncertain significance of ENG associated with HHT. The missense swap of alanine for valine at position 218 (Ala218Val) was characterized through computational metrics from in silico pathogenicity prediction tools, conservation analysis, and molecular dynamics simulation (MDS). The structural residue is highly conserved over multiple species and buried. The missense swap resulted in a difference in movement from the wild type according to MDS in a simulated aqueous environment. Therefore, it is predicted to be likely pathogenic.