ClinVar Genomic variation as it relates to human health

The KRT10 c.466C>T variant is predicted to result in the amino acid substitution p.Arg156Cys. This variant has been frequently reported in individuals with epidermolytic hyperkeratosis (see for example Syder et al. 1994. PubMed ID: 7512983; Saeki et al. 2002. PubMed ID: 11990254; Haruna et al. 2007. PubMed ID: 17683385; Bygum et al. 2013. PubMed ID: 22930352; Severino-Freire et al. 2017. PubMed ID: 27722766; Kono et al. 2017. PubMed ID: 28532675; Cheng et al. 2020. PubMed ID: 31953843). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

Located within the 1A domain helix initiation motif that is intolerant to change; 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); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 11990254, 17683385, 7509230, 7512983, 7526210, 28532675, 27722766, 22930352, 27535533, 31953843, 18033728, 24077912, 33081034)

The KRT10 c.466C>T (Arg156Cys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals affected by ichthyosis (Paller AS et al., PMID: 7526210; Cheraghlou S et al., PMID: 32045015; Bygum A et al., PMID: 22930352; Kono M et al., PMID: 28532675; Syder AJ et al., PMID: 7512983; Mirza H et al., PMID: 26176760; Haruna K et al., PMID: 17683385; Rothnagel JA et al., PMID: 7509230; Diociaiuti A et al., PMID: 33081034). This variant has been reported in the ClinVar database as a pathogenic germline variant by multiple submitters and a likely pathogenic somatic variant by one submitter (ClinVar ID: 14576) and, in one case, in the cancer database COSMIC (ID: COSV99509833). This variant is absent from the general population, indicating that it is not a common variant (gnomAD v.3.1.2). The KRT10 c.466C>T (Arg156Cys) variant resides within an intermediate filament rod domain, amino acids 145-454, of KRT10 that is defined as a critical functional domain (Porter RM et al., PMID: 12711220; Rothnagel JA et al., PMID: 1380725). Functional studies show that this variant results in filament assembly disruption, leading to cell fragility (Syder AJ et al., PMID: 7512983; Mirza H et al., PMID: 26176760). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to KRT10 function. Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the KRT10 c.466C>T (Arg156Cys) variant is classified as pathogenic.

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg156 amino acid residue in KRT10. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1381287, 21271994). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KRT10 function (PMID: 7512983, 26176760). 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) performed at Invitae indicates that this missense variant is expected to disrupt KRT10 protein function. ClinVar contains an entry for this variant (Variation ID: 14576). This missense change has been observed in individual(s) with autosomal dominant KRT10 related conditions (PMID: 21271994, 22930352, 28532675). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 156 of the KRT10 protein (p.Arg156Cys).