NM_000424.4(KRT5):c.556G>T (p.Val186Leu) AND Epidermolysis bullosa simplex, Koebner type

Significance: Pathogenic
ClinVar: RCV000015758

Variant: NM_000424.4(KRT5):c.556G>T (p.Val186Leu)

Type: Variant
Allele: NM_000424.4(KRT5):c.556G>T (p.Val186Leu) 29691
Type: single nucleotide variant
Location: Chr12: 52519160 - assembly GRCh38
Chr12: 52912944 - assembly GRCh37
References: dbSNP: 121912475
OMIM: 148040.0014
UniProtKB: P13647#VAR_013829


Disease: Epidermolysis bullosa simplex, Koebner type


    In a family with severe generalized EBS (131900), Liovic et al. (2001) found a novel K5 mutation, val186 to leu (V186L), that produced a conservative amino acid change at position 18 of the 1A helix. The phenotype was unexpectedly severe for the location of the mutation, which lies outside the consensus helix initiation motif mutation hotspot, and other mutations at this position have been associated with Weber-Cockayne (mild) epidermolysis bullosa simplex (131800) only. De novo K5/K14 (148066) (mutant and wildtype) filament assembly in cultured cells was studied to determine the effect of this mutation on filament polymerization and stability. To visualize the structural impact of this mutation and to compare it with an analogous mutation causing mild disease, Liovic et al. (2001) generated a computer model of the 1A region of the K5/K14 coiled-coil. The results showed a high level of concordance between genetic, cell culture, and molecular modeling data, suggesting that even a conservative substitution can cause severe dysfunction in a structural protein, depending on the size and structure of the amino acid involved.