ClinVar Miner

Submissions for variant NM_005555.4(KRT6B):c.1414G>A (p.Glu472Lys) (rs60627726)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000057023 SCV000321847 pathogenic not provided 2016-06-17 criteria provided, single submitter clinical testing The E472K variant in the KRT6B gene has been previously reported in patients with pachyonychia congenita (Smith et al., 1998; Wilson et al., 2014). 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 mutational 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 in nearby residues (L469R) 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 hyperkeratosis (Chamcheu et al., 2011). Additionally, the KRT6B gene has a low rate of benign missense variant with missense variants being a common mechanism of disease. Therefore, we consider E472K to be pathogenic.
OMIM RCV000015739 SCV000036004 pathogenic Pachyonychia congenita 4 2005-10-01 no assertion criteria provided literature only
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057023 SCV000088136 not provided not provided no assertion provided not provided

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