Description
The I467T pathogenic variant has been reported previously in association with epidermolysis bullosa simplex (Irvine et al. 1997, Arin et al. 2010). It was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs within a known mutational hotspot region helix termination motif of the coil 2B region of the protein that is highly conserved across all species and among all members of the keratin family. Many other pathogenic variants in patients with epidermolysis bullosa simplex have been reported in the same residue (I467K, I467L, I467M) and in nearby residues (L463P, E466D, T469P, Y470H, R471C, R471H) according to the Human Gene Mutation Database (Stenson et al., 2014). It is well established that keratin gene mutations affecting the residues at the ends of the central rod domains of the keratin proteins (helix initiation and termination motifs) interfere with proper keratin intermediate filament assembly and function, resulting in skin fragility, blistering and/or hyperkeratosis (Chamcheu et al., 2011). Therefore, I467T is pathogenic and consistent with a diagnosis of epidermolysis bullosa simplex (EBS).
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | yes | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
