ClinVar Genomic variation as it relates to human health

The R127C pathogenic variant has been reported in several multi-generation families with focal non-epidermolytic palmoplantar keratoderma (FNEPPK) as well as pachyonychia congenita (PC) (Shamsher, et al., 1995; Fu et al., 2011). In contrast, it was not observed in any of 6,500 control individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R127C 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 initiation 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 the same codon (R127S/G/H/P) or nearby residues (Q122P, L124H/R/P, N125D/S, L128Q/P, L132P) 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). Therefore, we consider R127C to be pathogenic.

The KRT16 c.379C>T variant is predicted to result in the amino acid substitution p.Arg127Cys. This variant has been reported in individuals with non-epidermolytic palmoplantar keratoderma (Shamsher et al. 1995. PubMed ID: 8595410) and in individuals with pachyonychia congenita (Fu et al. 2010. PubMed ID: 21160496; Samuelov et al. 2020. PubMed ID: 31823354; Smith et al. 2005. PubMed ID: 16250206). Of note, other variants impacting p.Arg127 have also been reported in individuals with pachyonychia congenita (Fu et al. 2010. PubMed ID: 21160496). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare, and is reported as pathogenic by several laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/14601/). This variant is interpreted as pathogenic.

Criteria applied: PM5_STR,PS4_MOD,PM1,PP1,PP3

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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 KRT16 protein function. ClinVar contains an entry for this variant (Variation ID: 14601). This variant is also known as R10C. This missense change has been observed in individual(s) with pachyonychia congenita (PMID: 8595410, 31823354). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 127 of the KRT16 protein (p.Arg127Cys).

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, gain of function and dominant negative have been suggested (PMID: 22336941). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (4 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by several clinical laboratories in ClinVar, and has been observed in several families with pachyonychia congenita and palmoplantar keratoderma (PMIDs: 24611874, 8595410) (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been seen to segregate with disease in ten affected members of one family with palmoplantar keratoderma (PMID: 8595410). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign