Submissions for variant NM_000421.5(KRT10):c.466C>T (p.Arg156Cys)

dbSNP: rs58852768

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000056496	SCV000490590	pathogenic	not provided	2021-12-30	criteria provided, single submitter	clinical testing	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)
Fulgent Genetics, Fulgent Genetics	RCV000763396	SCV000894117	pathogenic	Epidermolytic ichthyosis; Congenital reticular ichthyosiform erythroderma; Annular epidermolytic ichthyosis	2018-10-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000056496	SCV002016400	pathogenic	not provided	2020-11-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056496	SCV002119181	pathogenic	not provided	2022-11-03	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 14576). 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. Experimental studies have shown that this missense change affects KRT10 function (PMID: 7512983, 26176760). 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. For these reasons, this variant has been classified as Pathogenic. 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 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). This variant is not present in population databases (gnomAD no frequency).
PreventionGenetics, part of Exact Sciences	RCV003398521	SCV004119931	pathogenic	KRT10-related disorder	2022-12-06	criteria provided, single submitter	clinical testing	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.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV003458335	SCV004176923	pathogenic	Epidermolytic nevus	2023-10-10	criteria provided, single submitter	clinical testing	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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV004797762	SCV005419405	pathogenic	Autosomal dominant epidermolytic ichthyosis	2024-12-04	criteria provided, single submitter	clinical testing
3billion	RCV004593967	SCV005904800	pathogenic	Epidermolytic hyperkeratosis 2A, autosomal dominant	2024-03-12	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.94 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.89 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014576 /PMID: 7509230).Different missense changes at the same codon (p.Arg156Gly, p.Arg156His, p.Arg156Leu, p.Arg156Pro, p.Arg156Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014573, VCV000066176 /PMID: 11558869, 1381287, 7507152, 7509230). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM	RCV004593967	SCV000035940	pathogenic	Epidermolytic hyperkeratosis 2A, autosomal dominant	1994-02-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000056496	SCV000087607	not provided	not provided		no assertion provided	not provided
Yale Center for Mendelian Genomics, Yale University	RCV001849267	SCV002106701	likely pathogenic	Epidermolytic acanthoma	2020-02-19	no assertion criteria provided	literature only