Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000057037 | SCV000321822 | pathogenic | not provided | 2020-04-13 | criteria provided, single submitter | clinical testing | Located within a known hotspot region, the helix initiation motif in the 1A domain, which is intolerant to change and highly conserved across all species and among all members of the keratin family (Chamcheu et al., 2011); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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 (Duverger et al., 2019); Reported as pathogenic in ClinVar and the KIF database (VCV000014602; Landrum et al., 2016; Szeverenyi et al., 2008); This variant is associated with the following publications: (PMID: 24491404, 8595410, 30009827, 28794556, 30859684, 31021398, 16250206, 21160496, 17719747, 31823354) |
| 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 | |
| Invitae | RCV000057037 | SCV002234490 | pathogenic | not provided | 2023-08-28 | criteria provided, single submitter | clinical testing | This variant is also known as N8S. ClinVar contains an entry for this variant (Variation ID: 14602). Advanced 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 at Invitae 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. This missense change has been observed in individuals with pachyonychia congenita (PMID: 8595410, 24491404, 31823354; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). 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). |
| 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 |