ClinVar Miner

Submissions for variant NM_005554.4(KRT6A):c.1414G>A (p.Glu472Lys) (rs60554162)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000056998 SCV000321844 pathogenic not provided 2017-05-11 criteria provided, single submitter clinical testing The E472K pathogenic variant in the KRT6A gene has been previously reported in association with Pachyonychia Congenita (PC) (Terrinoni et al., 2001; Wilson et al., 2014; Harris et al., 2012). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. E472K is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs within a known hotspot region (helix termination motif) that is highly conserved across all species and among all members of the keratin family. Many other pathogenic variants in patients with pachyonychia congenita have been reported at the same residue (E472D) and in nearby residues (L468P/Q, L469R) according to the Human Gene Mutation Database (Stenson et al., 2014). It is well established that keratin gene variants 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 hyperkeratosis (Chamcheu et al., 2011). Therefore, we consider E472K to be pathogenic.
OMIM RCV000015742 SCV000036007 pathogenic Pachyonychia congenita 3 2001-12-01 no assertion criteria provided literature only
Epithelial Biology; Institute of Medical Biology, Singapore RCV000056998 SCV000088111 not provided not provided no assertion provided not provided

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