ClinVar Miner

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

dbSNP: rs58852768
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Total submissions: 9
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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 Bullous ichthyosiform erythroderma; 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
Invitae RCV000056496 SCV002119181 pathogenic not provided 2022-11-03 criteria provided, single submitter clinical testing 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).
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.
OMIM RCV000015677 SCV000035940 pathogenic Bullous ichthyosiform erythroderma 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

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