ClinVar Genomic variation as it relates to human health

The missense variant p.R156H in KRT10 (NM_000421.5) has been previously reported with epidermolytic hyperkeratosis in multiple affected patients (Virtanen M et al; Li et al). The variant is situated in a hotspot and other mutations affecting the same codon have been reported to be disease causing (Haruna et al; Bygum et al). The variant has been submitted to ClinVar as Pathogenic. The p.R156H variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a small physicochemical difference between arginine and histidine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.R156H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 156 of KRT10 is conserved in all mammalian species. The nucleotide c.467 in KRT10 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

Located within the 1A domain helix initiation motif that is intolerant to change; variants affecting residues at the ends of the central rod domains of 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 a 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: 11558869, 24001792, 21811984, 25214791, 1381287, 7509230, 31046801, 31909138, 31953843, 18033728, 24077912)

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: 7512983, 22930352, 26176760, 28532675; Invitae). 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: 1381287). 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: 14573). This missense change has been observed in individuals with autosomal dominant KRT10-related conditions (PMID: 1381287, 24001792). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs58075662, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 156 of the KRT10 protein (p.Arg156His).

The KRT10 c.467G>A (p.Arg156His) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals affected by ichthyosis (Cheng J et al., PMID: 1381287; Diociaiuti A et al., PMID: 33081034; Haruna K et al., PMID: 17683385; Li Z et al., PMID: 25214791; Elango T et al., PMID: 29784039; Mayuzumi N et al., PMID: 11204523). This variant has been reported in the ClinVar database as a pathogenic germline variant by multiple submitters (ClinVar ID: 14573) and in two cases in the cancer database COSMIC as a somatic variant (ID: COSV54091758). This variant is absent from the general population, indicating that it is not a common variant (gnomAD v.4.0.0). The KRT10 c.467G>A (p.Arg156His) variant resides within an intermediate filament rod domain of KRT10 that is defined as a critical functional domain (Porter RM et al., PMID: 12711220; Rothnagel JA et al., PMID: 1380725). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to KRT10 function. In support of this prediction, functional studies show that this variant acts in a dominant negative fashion to generate the aberrant keratin filament networks (Cheng J et al., PMID: 1381287). Another variant in the same codon, c.466C>T (Arg156Cys), has been reported in multiple individuals affected by ichthyosis and is considered pathogenic (Mirza H et al., PMID: 26176760; ClinVar ID: 14576). 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.467G>A (p.Arg156His) variant is classified as pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with ichthyosis with confetti (MIM#609165) and epidermolytic hyperkeratosis (MIM#113800), respectively. Frameshift variants resulting in an arginine-rich C-terminal peptide have been reported with a dominant negative mechanism, while those predicted to undergo nonsense-mediated decay (NMD) have a loss of function mechanism (PMIDs: 20798280, 31638346). A toxic gain of function has also been demonstrated for one missense variant associated with dominant epidermolytic hyperkeratosis (MIM#113800) (PMID: 26176760). (I) 0108 - This gene is associated with both recessive and dominant disease. Individuals with biallelic variants predicted to undergo NMD have been reported with recessive disease (PMIDs: 18219278, 16505000). Individuals with frameshift variants affecting the last exon, missense variants and splice variants have all been reported with dominant disease (PMIDs: 26176760, 20798280, 31638346). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been noted for annular epidermolytic ichthyosis (MIM#1607602) (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0254 - This variant is confirmed mosaic. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and very highly conserved with a minor amino acid change. (SP) 0600 - Variant is located in the annotated filament coiled coil domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least ten individuals across different populations, with or without a family history of epidermolytic ichthyosis (CinVar, PMIDs: 21271994, 25214791, 33081034). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The KRT10 c.467G>A variant is predicted to result in the amino acid substitution p.Arg156His. This variant has been previously reported, in the heterozygous state, in individuals with epidermolytic hyperkeratosis or hereditary ichthyosis (Cheng et al. 1992. PubMed ID: 1381287; Virtanen et al. 2001. PubMed ID: 11558869; Li et al. 2014. PubMed ID: 25214791; Cheng et al. 2020. PubMed ID: 31953843). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.