Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000255266 | SCV000321846 | pathogenic | not provided | 2018-04-20 | criteria provided, single submitter | clinical testing | The E472K variant in the KRT6C gene has been reported previously in multiple families with KRT6C-related palmoplantar keratoderma with or without nail dystrophy (Wilson et al., 2010; Akasaka et al., 2011). In vitro functional studies demonstrated that the presence of the E472K variant results in a dose-dependent collapse of the heterodimer keratin filament network and formation of large aggregates containing the co-expressed keratins K14 and K6C (Kubo et al., 2013). The E472K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E472K variant is a non-conservative amino acid substitution, which is located within the 2B helix termination motif of keratin 6C that is intolerant to change (Kubo et al., 2013). We therefore interpret E472K as a pathogenic variant. |
| Fulgent Genetics, |
RCV000114418 | SCV002811562 | likely pathogenic | Palmoplantar keratoderma, nonepidermolytic, focal or diffuse | 2021-10-29 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000255266 | SCV005836046 | pathogenic | not provided | 2024-10-05 | 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 KRT6C protein (p.Glu472Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with palmoplantar keratoderma (PMID: 21801157, 24611874; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126527). 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 KRT6C protein function. Experimental studies have shown that this missense change affects KRT6C function (PMID: 23662636). For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000114418 | SCV000148350 | pathogenic | Palmoplantar keratoderma, nonepidermolytic, focal or diffuse | 2013-07-01 | no assertion criteria provided | literature only |