ClinVar Miner

Submissions for variant NM_005557.4(KRT16):c.374A>G (p.Asn125Ser) (rs60723330)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000057037 SCV000321822 pathogenic not provided 2016-02-22 criteria provided, single submitter clinical testing The N125S pathogenic variant in the KRT16 gene has been published previously in association with pachyonychia congenita (PC) (Liao et al., 2007; Fu et al., 2011; Smith et al., 2005; Shamsher et al., 1995). 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. N125S is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs within a known 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 at the same codon (N125D) and in nearby residues (M121T/K, Q122P, L124R/H/P, R127S/C/G/H/P, L128Q/ P) 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 N125S to be pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763397 SCV000894119 pathogenic Pachyonychia congenita 1; Palmoplantar keratoderma, nonepidermolytic, focal 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000015706 SCV000035971 pathogenic Palmoplantar keratoderma, nonepidermolytic, focal 2005-10-01 no assertion criteria provided literature only
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057037 SCV000088150 not provided not provided no assertion provided not provided
OMIM RCV000144080 SCV000189155 pathogenic Pachyonychia congenita 1 2005-10-01 no assertion criteria provided literature only

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