ClinVar Genomic variation as it relates to human health
NM_000422.3(KRT17):c.280C>T (p.Arg94Cys)
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.
Pathogenic(4); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000422.3(KRT17):c.280C>T (p.Arg94Cys)
Variation ID: 14591 Accession: VCV000014591.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.2 17: 41624230 (GRCh38) [ NCBI UCSC ] 17: 39780482 (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 Oct 19, 2013 May 12, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000422.3:c.280C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000413.1:p.Arg94Cys missense NC_000017.11:g.41624230G>A NC_000017.10:g.39780482G>A NG_008625.1:g.5401C>T NG_009090.2:g.167483C>T LRG_1345:g.5401C>T LRG_1345t1:c.280C>T LRG_1345p1:p.Arg94Cys LRG_401:g.167483C>T Q04695:p.Arg94Cys - Protein change
- R94C
- Other names
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- Canonical SPDI
- NC_000017.11:41624229: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
Help
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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KRT17 | - | - |
GRCh38 GRCh37 |
125 | 131 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Mar 29, 2024 | RCV000015694.30 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jul 10, 2022 | RCV000056513.21 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 1, 1998 | RCV000114415.4 |
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
Help
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
Help
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
Help
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
(Jun 19, 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: SCV003441855.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 14591). This missense change has been observed in individuals with pachyonychia congenita and/or steatocystoma multiplex (PMID: 9767294, 25946540, 26165312, 29218738, 31823354). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs58730926, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 94 of the KRT17 protein (p.Arg94Cys). (less)
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Pathogenic
(Dec 01, 2021)
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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: SCV002063611.15
First in ClinVar: Jan 29, 2022 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jul 10, 2022)
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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: SCV000321827.8
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Located within the helix initiation in 1A domain that is intolerant of change; Not observed at significant frequency in large population cohorts (gnomAD); In silico … (more)
Located within the helix initiation in 1A domain that is intolerant of change; Not observed at significant frequency in large population cohorts (gnomAD); 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: 22336949, 31823354, 9767294, 29218738, 26165312, 25946540) (less)
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Uncertain significance
(Mar 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Steatocystoma multiplex
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004808115.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Feb 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Steatocystoma multiplex
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812337.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in KRT17 is predicted to replace arginine with cysteine at codon 94, p.(Arg94Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), … (more)
This sequence change in KRT17 is predicted to replace arginine with cysteine at codon 94, p.(Arg94Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the intermediate filament rod domain, a region (amino acids 92 - 95) that is a mutational hotspot (ClinVar). There is a large physicochemical difference between arginine and cysteine. The highest population minor allele frequency in gnomAD v3.1 is 0.02% (1/5,170 alleles) in the East Asian population, and another singleton is present in the African/African-American population (1/41,428 alleles). This variant has been reported in at least six probands with pachyonychia congenita or steatocystoma multiplex, and segregates with disease in multiple families (PMID: 9767294, 11809119, 22336949, 26165312). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 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
(Sep 01, 1998)
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no assertion criteria provided
Method: literature only
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STEATOCYSTOMA MULTIPLEX
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035959.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 13, 2016 |
Comment on evidence:
Covello et al. (1998) described 2 unrelated kindreds with the identical missense arg94-to-cys (R94C) mutation in the 1A domain of keratin-17. However, whereas affected members … (more)
Covello et al. (1998) described 2 unrelated kindreds with the identical missense arg94-to-cys (R94C) mutation in the 1A domain of keratin-17. However, whereas affected members of 1 kindred had the classic features of Jackson-Lawler pachyonychia congenita (PC2; 167210), affected persons in the other family had the steatocystoma multiplex phenotype (184500). The PC2 family consisted of affected mother and son; the affected steatocystoma multiplex family had affected mother, son, and daughter. The proband in the first family had a history of subcutaneous yellow nodules on the flexor surfaces of the arms, abdomen, and legs since puberty. She also had thickened nails of the feet. In the steatocystoma multiplex family, the 41-year-old Dutch Caucasian mother presented at an outpatient clinic because of what she described as 'acne present from puberty.' The number of lesions had increased with age; in addition to the face, lesions were present on the abdomen, arms, and legs. Her 4-year-old daughter and 11-year-old son were developing similar skin problems. Multiple nodules with varying diameter were found in the areas mentioned. None of the affected persons showed any nail changes or any other skin, hair, or mucosal abnormalities. (less)
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Pathogenic
(Sep 01, 1998)
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no assertion criteria provided
Method: literature only
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PACHYONYCHIA CONGENITA 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000148347.2
First in ClinVar: Apr 19, 2014 Last updated: Oct 13, 2016 |
Comment on evidence:
Covello et al. (1998) described 2 unrelated kindreds with the identical missense arg94-to-cys (R94C) mutation in the 1A domain of keratin-17. However, whereas affected members … (more)
Covello et al. (1998) described 2 unrelated kindreds with the identical missense arg94-to-cys (R94C) mutation in the 1A domain of keratin-17. However, whereas affected members of 1 kindred had the classic features of Jackson-Lawler pachyonychia congenita (PC2; 167210), affected persons in the other family had the steatocystoma multiplex phenotype (184500). The PC2 family consisted of affected mother and son; the affected steatocystoma multiplex family had affected mother, son, and daughter. The proband in the first family had a history of subcutaneous yellow nodules on the flexor surfaces of the arms, abdomen, and legs since puberty. She also had thickened nails of the feet. In the steatocystoma multiplex family, the 41-year-old Dutch Caucasian mother presented at an outpatient clinic because of what she described as 'acne present from puberty.' The number of lesions had increased with age; in addition to the face, lesions were present on the abdomen, arms, and legs. Her 4-year-old daughter and 11-year-old son were developing similar skin problems. Multiple nodules with varying diameter were found in the areas mentioned. None of the affected persons showed any nail changes or any other skin, hair, or mucosal abnormalities. (less)
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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: SCV000087624.1
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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Revisiting pachyonychia congenita: a case-cohort study of 815 patients. | Samuelov L | The British journal of dermatology | 2020 | PMID: 31823354 |
A recurrent mutation in the KRT17 gene responsible for severe steatocystoma multiplex in a large Chinese family. | Wang J | Clinical and experimental dermatology | 2018 | PMID: 29218738 |
[Clinical and molecular findings of pachyonychia congenita type 2 (PC-2)]. | Cammarata-Scalisi F | Gaceta medica de Mexico | 2015 | PMID: 25946540 |
Homozygous dominant missense mutation in keratin 17 leads to alopecia in addition to severe pachyonychia congenita. | Wilson NJ | The Journal of investigative dermatology | 2012 | PMID: 22336949 |
[Keratin 17 gene mutation in patients with steatocystoma multiplex]. | Wang X | Zhonghua yi xue za zhi | 2001 | PMID: 11809119 |
Keratin 17 mutations cause either steatocystoma multiplex or pachyonychia congenita type 2. | Covello SP | The British journal of dermatology | 1998 | PMID: 9767294 |
Text-mined citations for rs58730926 ...
HelpRecord last updated May 12, 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.