ClinVar Miner

Submissions for variant NM_005557.4(KRT16):c.379C>T (p.Arg127Cys) (rs59856285)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000057038 SCV000321823 pathogenic not provided 2016-07-25 criteria provided, single submitter clinical testing The R127C pathogenic variant has been reported in several multi-generation families with focal non-epidermolytic palmoplantar keratoderma (FNEPPK) as well as pachyonychia congenita (PC) (Shamsher, et al., 1995; Fu et al., 2011). In contrast, it was not observed in any of 6,500 control individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R127C 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 initiation 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 the same codon (R127S/G/H/P) or nearby residues (Q122P, L124H/R/P, N125D/S, L128Q/P, L132P) 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). Therefore, we consider R127C to be pathogenic.
Institute of Human Genetics,Klinikum rechts der Isar RCV000578284 SCV000680280 pathogenic Pachyonychia congenita 1 2017-12-11 criteria provided, single submitter clinical testing
OMIM RCV000015705 SCV000035970 pathogenic Palmoplantar keratoderma, nonepidermolytic, focal 2005-10-01 no assertion criteria provided literature only
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057038 SCV000088151 not provided not provided no assertion provided not provided

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