Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000483744 | SCV000571007 | likely pathogenic | not provided | 2016-07-20 | criteria provided, single submitter | clinical testing | To our knowledge, the F189S variant in the KRT2 gene has not been reported previously as a pathogenic variant, nor as a benign variant. It was also 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. F189S 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 hotspot region (helix initiation motif) that is highly conserved across all species and among all members of the keratin family. Many other pathogenic missense variants in patients with superficial epidermolytic ichthyosis have been reported in nearby residues (N186Y/D/K/S) according to the Human Gene Mutation Database (Stenson et al., 2014). It is well established that keratin gene variants 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 skin fragility and/or hyperkeratosis (Chamcheu et al., 2011). Therefore, F189S is considered to be likely pathogenic, however the possibility it may be a rare benign variant cannot be excluded. |
| Prevention |
RCV003401546 | SCV004111052 | uncertain significance | KRT2-related condition | 2023-03-13 | criteria provided, single submitter | clinical testing | The KRT2 c.566T>C variant is predicted to result in the amino acid substitution p.Phe189Ser. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant has been interpreted as likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/421717/). Nearby missense variant (p.Asn186Asp, p.Asn186Tyr, p.Asn186Ser, p.Asn186Lys) have been reported as pathogenic (Human Gene Mutation Database). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |