Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
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. |
| Fulgent Genetics, |
RCV000015739 | SCV002776033 | pathogenic | Pachyonychia congenita 4 | 2022-03-07 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000057023 | SCV003441263 | pathogenic | not provided | 2024-04-24 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 472 of the KRT6B protein (p.Glu472Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pachyonychia congenita (PMID: 9618173, 33301203). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14633). 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 KRT6B protein function. For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000015739 | SCV000036004 | pathogenic | Pachyonychia congenita 4 | 2005-10-01 | no assertion criteria provided | literature only | |
| Epithelial Biology; Institute of Medical Biology, |
RCV000057023 | SCV000088136 | not provided | not provided | no assertion provided | not provided |