Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000057037 | SCV000321822 | pathogenic | not provided | 2024-11-14 | criteria provided, single submitter | clinical testing | Immunostaining of tooth enamel from a PC patient with the N125S variant showed abnormal K16 protein aggregation and atypical cracks within the inner enamel, and in vitro expression demonstrated altered keratin intermediate filament assembly and intracellular clumping (PMID: 30009827); Multiple pathogenic missense variants have been reported in this codon (N125G and N125D) and in nearby residues (Q122R, Q122P, L124H, L124P, L124R, R127G, R127S, R127C, R127P, R127H, L128Q, L128P) in association with KRT16-related disorders in the Human Gene Mutation Database (HGMD); Located in the highly conserved helix initiation motif of the alpha-helical rod domain, which is intolerant to change; variants in this motif interfere with proper keratin intermediate filament assembly and function, resulting in skin fragility and/or hyperkeratosis (PMID: 21176769); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24491404, 8595410, 28794556, 30859684, 31021398, 16250206, 21160496, 31823354, 21326300, 17719747, 38191074, 30009827, 21176769) |
| Fulgent Genetics, |
RCV000763397 | SCV000894119 | pathogenic | Pachyonychia congenita 1; Palmoplantar keratoderma, nonepidermolytic, focal 1 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Institute of Medical Genetics and Applied Genomics, |
RCV000057037 | SCV001447598 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000057037 | SCV002234490 | pathogenic | not provided | 2025-02-03 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 125 of the KRT16 protein (p.Asn125Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pachyonychia congenita (PMID: 8595410, 24491404, 31823354; internal data). It has also been observed to segregate with disease in related individuals. This variant is also known as N8S. ClinVar contains an entry for this variant (Variation ID: 14602). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KRT16 protein function. This variant disrupts the p.Asn125 amino acid residue in KRT16. Other variant(s) that disrupt this residue have been observed in individuals with KRT16-related conditions (PMID: 22668561), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000015706 | SCV000035971 | pathogenic | Palmoplantar keratoderma, nonepidermolytic, focal 1 | 2005-10-01 | no assertion criteria provided | literature only | |
| Epithelial Biology; Institute of Medical Biology, |
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 |