Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However in keratin proteins, missense at the start and end of the a-helical rod domain (within 1A and 2B) within the helix boundary motif domains are expected to interfere with assembly of intermediate filaments (PMIDs: 24611874, 14714564). In addition, induction of keratin K17 expression has been reported in psoriasis (PMID: 29784039). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. It is located in the coil 1A region within the rod domain (PMID: 29784039), where reported missense variants are clustered (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple unrelated individuals with steatocystoma multiplex or pachyonychia congenita 2 (PMIDs: 9008238, 11886499, 19470054). It has also been reported as pathogenic once in ClinVar. (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
ClinVar Genomic variation as it relates to human health
NM_000422.3(KRT17):c.281G>A (p.Arg94His)
Germline
Classification
Help
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.
(8)
Help
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/Likely pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000422.3(KRT17):c.281G>A (p.Arg94His)
Variation ID: 14590 Accession: VCV000014590.34
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q21.2 17: 41624229 (GRCh38) [ NCBI UCSC ] 17: 39780481 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Dec 22, 2024 Jul 1, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000422.3:c.281G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000413.1:p.Arg94His missense NC_000017.11:g.41624229C>T NC_000017.10:g.39780481C>T NG_008625.1:g.5402G>A NG_009090.2:g.167484G>A LRG_1345:g.5402G>A LRG_1345t1:c.281G>A LRG_1345p1:p.Arg94His LRG_401:g.167484G>A Q04695:p.Arg94His - Protein change
- R94H
- Other names
- -
- Canonical SPDI
- NC_000017.11:41624228:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
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. |
|||
| KRT17 | - | - |
GRCh38 GRCh37 |
135 | 142 | |
Conditions - Germline
| Condition
Help
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, single submitter
|
Feb 2, 2022 | RCV000015692.29 | |
| Pathogenic (1) |
no assertion criteria provided
|
Dec 1, 2001 | RCV000114414.4 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 1, 2023 | RCV000056515.26 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 23, 2021 | RCV002496374.3 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Feb 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Steatocystoma multiplex
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768338.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However in keratin proteins, missense at the start and end of the a-helical rod domain (within 1A and 2B) within the helix boundary motif domains are expected to interfere with assembly of intermediate filaments (PMIDs: 24611874, 14714564). In addition, induction of keratin K17 expression has been reported in psoriasis (PMID: 29784039). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. It is located in the coil 1A region within the rod domain (PMID: 29784039), where reported missense variants are clustered (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple unrelated individuals with steatocystoma multiplex or pachyonychia congenita 2 (PMIDs: 9008238, 11886499, 19470054). It has also been reported as pathogenic once in ClinVar. (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(Jul 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004297770.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 94 of the KRT17 protein (p.Arg94His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 94 of the KRT17 protein (p.Arg94His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Steatocystoma multiple (PMID: 9008238). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14590). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KRT17 protein function. This variant disrupts the p.Arg94 amino acid residue in KRT17. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9767294, 25946540, 26165312, 29218738). 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. (less)
|
|
|
Pathogenic
(Dec 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001250280.27
First in ClinVar: May 12, 2020 Last updated: Dec 22, 2024 |
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Oct 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Pachyonychia congenita 2
Steatocystoma multiplex
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002809853.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Pachyonychia congenita 2
Steatocystoma multiplex
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: yes
Allele origin:
germline
|
Juno Genomics, Hangzhou Juno Genomics, Inc
Accession: SCV005417196.1
First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024 |
Comment:
PM2_Supporting+PP3_Strong+PM5+PS4_Supporting+PP1+PP4
|
|
|
Pathogenic
(Dec 01, 2001)
|
no assertion criteria provided
Method: literature only
|
STEATOCYSTOMA MULTIPLEX
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035957.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 29, 2024 |
Comment on evidence:
In a kindred in which 8 individuals in 3 generations had steatocystoma multiplex (184500), Smith et al. (1997) found heterozygosity for a purine transition, c.429G-A, … (more)
In a kindred in which 8 individuals in 3 generations had steatocystoma multiplex (184500), Smith et al. (1997) found heterozygosity for a purine transition, c.429G-A, causing a predicted arg94-to-his (R94H) substitution. The mutation occurred in residue 10 of the KRT17 helix initiation peptide and potentially was a CpG deamination mutation. Although originally diagnosed with steatocystoma multiplex, on restudy some but not all of the patients were found to have mild nail changes compatible with those of pachyonychia congenita (see PC2, 167210). Terrinoni et al. (2001) reported this mutation in a patient with sporadic pachyonychia congenita (PC2). (less)
|
|
|
Pathogenic
(Dec 01, 2001)
|
no assertion criteria provided
Method: literature only
|
PACHYONYCHIA CONGENITA 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000148346.2
First in ClinVar: Apr 19, 2014 Last updated: Jun 29, 2024 |
Comment on evidence:
In a kindred in which 8 individuals in 3 generations had steatocystoma multiplex (184500), Smith et al. (1997) found heterozygosity for a purine transition, c.429G-A, … (more)
In a kindred in which 8 individuals in 3 generations had steatocystoma multiplex (184500), Smith et al. (1997) found heterozygosity for a purine transition, c.429G-A, causing a predicted arg94-to-his (R94H) substitution. The mutation occurred in residue 10 of the KRT17 helix initiation peptide and potentially was a CpG deamination mutation. Although originally diagnosed with steatocystoma multiplex, on restudy some but not all of the patients were found to have mild nail changes compatible with those of pachyonychia congenita (see PC2, 167210). Terrinoni et al. (2001) reported this mutation in a patient with sporadic pachyonychia congenita (PC2). (less)
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
Epithelial Biology; Institute of Medical Biology, Singapore
Accession: SCV000087626.1
First in ClinVar: Oct 19, 2013 Last updated: Oct 19, 2013 |
|
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 94 of the KRT17 protein (p.Arg94His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Steatocystoma multiple (PMID: 9008238). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14590). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KRT17 protein function. This variant disrupts the p.Arg94 amino acid residue in KRT17. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9767294, 25946540, 26165312, 29218738). 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.
Comment:
PM2_Supporting+PP3_Strong+PM5+PS4_Supporting+PP1+PP4
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. |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However in keratin proteins, missense at the start and end of the a-helical rod domain (within 1A and 2B) within the helix boundary motif domains are expected to interfere with assembly of intermediate filaments (PMIDs: 24611874, 14714564). In addition, induction of keratin K17 expression has been reported in psoriasis (PMID: 29784039). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. It is located in the coil 1A region within the rod domain (PMID: 29784039), where reported missense variants are clustered (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple unrelated individuals with steatocystoma multiplex or pachyonychia congenita 2 (PMIDs: 9008238, 11886499, 19470054). It has also been reported as pathogenic once in ClinVar. (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 94 of the KRT17 protein (p.Arg94His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Steatocystoma multiple (PMID: 9008238). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14590). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KRT17 protein function. This variant disrupts the p.Arg94 amino acid residue in KRT17. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9767294, 25946540, 26165312, 29218738). 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.
Comment:
PM2_Supporting+PP3_Strong+PM5+PS4_Supporting+PP1+PP4
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutational analysis of epidermal and hyperproliferative type I keratins in mild and moderate psoriasis vulgaris patients: a possible role in the pathogenesis of psoriasis along with disease severity. | Elango T | Human genomics | 2018 | PMID: 29784039 |
| 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 |
| Steatocystoma multiplex is associated with the R94C mutation in the KRTl7 gene. | Liu Q | Molecular medicine reports | 2015 | PMID: 26165312 |
| [Clinical and molecular findings of pachyonychia congenita type 2 (PC-2)]. | Cammarata-Scalisi F | Gaceta medica de Mexico | 2015 | PMID: 25946540 |
| The molecular genetic analysis of the expanding pachyonychia congenita case collection. | Wilson NJ | The British journal of dermatology | 2014 | PMID: 24611874 |
| Novel missense mutation of keratin in Chinese family with steatocystoma multiplex. | Wang JF | Journal of the European Academy of Dermatology and Venereology : JEADV | 2009 | PMID: 19470054 |
| In vivo alteration of the keratin 17 gene in hair follicles by oligonucleotide-directed gene targeting. | Fan W | Experimental dermatology | 2003 | PMID: 14714564 |
| Novel and recurrent mutations in the genes encoding keratins K6a, K16 and K17 in 13 cases of pachyonychia congenita. | Terrinoni A | The Journal of investigative dermatology | 2001 | PMID: 11886499 |
| Keratin 17 mutations cause either steatocystoma multiplex or pachyonychia congenita type 2. | Covello SP | The British journal of dermatology | 1998 | PMID: 9767294 |
| Missense mutations in keratin 17 cause either pachyonychia congenita type 2 or a phenotype resembling steatocystoma multiplex. | Smith FJ | The Journal of investigative dermatology | 1997 | PMID: 9008238 |
Text-mined citations for rs28928897 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Dec 22, 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.