ClinVar Genomic variation as it relates to human health
NM_000226.4(KRT9):c.487C>T (p.Arg163Trp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000226.4(KRT9):c.487C>T (p.Arg163Trp)
Variation ID: 2997 Accession: VCV000002997.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.2 17: 41571506 (GRCh38) [ NCBI UCSC ] 17: 39727758 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 May 12, 2024 May 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000226.4:c.487C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000217.2:p.Arg163Trp missense NC_000017.11:g.41571506G>A NC_000017.10:g.39727758G>A NG_008300.2:g.5553C>T P35527:p.Arg163Trp - Protein change
- R163W
- Other names
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- Canonical SPDI
- NC_000017.11:41571505:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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KRT9 | - | - |
GRCh38 GRCh37 |
179 | 185 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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May 19, 2023 | RCV000003132.15 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Dec 12, 2022 | RCV000056465.32 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2017 | RCV000626629.9 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Epidermolytic palmoplantar keratoderma, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004027777.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Criteria applied: PM5_STR,PP1_STR,PS4_MOD,PM1,PM2_SUP,PP3
Clinical Features:
Palmoplantar keratosis (present)
Sex: male
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Pathogenic
(Aug 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Epidermolytic palmoplantar keratoderma, 1
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002498673.2
First in ClinVar: Apr 11, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change in KRT9 is predicted to replace arginine with tryptophan at codon 163 (p.(Arg163Trp)). The arginine residue is highly conserved (100 vertebrates, UCSC), … (more)
This sequence change in KRT9 is predicted to replace arginine with tryptophan at codon 163 (p.(Arg163Trp)). The arginine residue is highly conserved (100 vertebrates, UCSC), and is an invariant residue in human type 1 keratins in the coil 1A alpha-helical segment of the intermediate filament rod domain (PMID: 7512862). There is a large physicochemical difference between arginine and tryptophan. This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in multiple probands with epidermolytic palmoplantar keratoderma, and segregates with the disease in multiple families (PMID: 7512862, 7523529). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PS4_Moderate, PM1, PM2_Supporting, PP3. (less)
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Pathogenic
(Jun 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001371122.19
First in ClinVar: Jul 16, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Likely pathogenic
(Jan 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Palmoplantar keratoderma
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000747330.1
First in ClinVar: May 12, 2018 Last updated: May 12, 2018 |
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Epidermolytic palmoplantar keratoderma, 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894118.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Oct 09, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000321849.7
First in ClinVar: Oct 09, 2016 Last updated: Apr 17, 2019 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); Located within the helix initiation motif within the 1A region of the rod domain, which … (more)
Not observed in large population cohorts (Lek et al., 2016); Located within the helix initiation motif within the 1A region of the rod domain, which is a well-known mutation hotspot intolerant to change; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19223272, 25299193, 23278372, 7512862, 22262370, 27864007, 30666268, 15564199, 10844507) (less)
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Pathogenic
(Dec 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003441882.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 2997). This missense change has been observed in individuals with epidermolytic palmoplantar keratoderma (PMID: 22262370). It … (more)
ClinVar contains an entry for this variant (Variation ID: 2997). This missense change has been observed in individuals with epidermolytic palmoplantar keratoderma (PMID: 22262370). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 163 of the KRT9 protein (p.Arg163Trp). 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 KRT9 protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 01, 2009)
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no assertion criteria provided
Method: literature only
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PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023290.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 17, 2023 |
Comment on evidence:
The numbering of this KRT9 mutation (R163W) is based on the numbering system used by Lu et al. (2003). Early reports designated this mutation ARG162TRP. … (more)
The numbering of this KRT9 mutation (R163W) is based on the numbering system used by Lu et al. (2003). Early reports designated this mutation ARG162TRP. In 5 unrelated German pedigrees with epidermolytic palmoplantar keratoderma (EPPK1; 144200), including the family originally described by Thost (1880) and the family previously studied by Reis et al. (1992) with linkage to chromosome 17q11-q23, Hennies et al. (1993) and Reis et al. (1994) identified heterozygosity for a C-T transition in exon 1 of the KRT9 gene, resulting in an arg162-to-trp substitution at a highly conserved residue in coil 1A of KRT9. The mutation cosegregated completely with disease in a large 6-generation EPPK family and was not found in 42 unrelated controls. Haplotype analysis showed that in 3 large EPPK families, the mutation cosegregated with the same haplotype, whereas the 2 other families carried different mutant haplotypes at the KRT9 locus, suggesting that the mutation occurred independently on different haplotypes, or, more probably, that the mutation is not of recent origin. Bonifas et al. (1994) found the same R162W mutation in a family with EPPK previously reported by Berth-Jones and Hutchinson (1989). These were, however, independent mutations because the R162W mutation reported by Reis et al. (1994) occurred on an allele with 23 CA repeats in the microsatellite in intron 4 of the KRT9 gene, whereas the mutant allele reported by Bonifas et al. (1994) contained 24 CA repeats. In 13 affected members of a 5-generation Taiwanese family with EPPK, 6 of whom also had knuckle pads, Chiu et al. (2007) identified heterozygosity for the R163W mutation. In a 4-generation southern Italian family in which 11 of 24 members had EPPK, 1 of whom also had knuckle pads, Codispoti et al. (2009) identified heterozygosity for the R163W mutation. Quantitative RT-PCR analysis of a knuckle-pad skin biopsy revealed an almost 90-fold increase in KRT9 expression compared to control. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001744854.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956833.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Epithelial Biology; Institute of Medical Biology, Singapore
Accession: SCV000087574.1
First in ClinVar: Oct 19, 2013 Last updated: Oct 19, 2013 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Knuckle pads, in an epidermal palmoplantar keratoderma patient with Keratin 9 R163W transgrediens expression. | Codispoti A | European journal of dermatology : EJD | 2009 | PMID: 19106041 |
Mutation of keratin 9 (R163W) in a family with epidermolytic palmoplantar keratoderma and knuckle pads. | Chiu HC | Journal of dermatological science | 2007 | PMID: 17074468 |
A novel mutation of keratin 9 in epidermolytic palmoplantar keratoderma combined with knuckle pads. | Lu Y | American journal of medical genetics. Part A | 2003 | PMID: 12838553 |
Mutations of keratin 9 in two families with palmoplantar epidermolytic hyperkeratosis. | Bonifas JM | The Journal of investigative dermatology | 1994 | PMID: 7523529 |
Keratin 9 gene mutational heterogeneity in patients with epidermolytic palmoplantar keratoderma. | Hennies HC | Human genetics | 1994 | PMID: 7516304 |
Keratin 9 gene mutations in epidermolytic palmoplantar keratoderma (EPPK). | Reis A | Nature genetics | 1994 | PMID: 7512862 |
Mapping of a gene for epidermolytic palmoplantar keratoderma to the region of the acidic keratin gene cluster at 17q12-q21. | Reis A | Human genetics | 1992 | PMID: 1385292 |
A family with palmoplantar epidermolytic hyperkeratosis. | Berth-Jones J | Clinical and experimental dermatology | 1989 | PMID: 2531643 |
Thost, A. Ueber erbliche Ichthyosis palmaris et plantaris cornea. Dissertation: Heidelberg (pub.) 1880. | - | - | - | - |
Text-mined citations for rs59616921 ...
HelpRecord last updated May 27, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.