VCV000014587.35 - ClinVar

NM_000422.3(KRT17):c.275A>G (p.Asn92Ser)

Germline

Classification

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)

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

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.275A>G (p.Asn92Ser)

Variation ID: 14587 Accession: VCV000014587.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.2 17: 41624235 (GRCh38) [ NCBI UCSC ] 17: 39780487 (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	Jun 29, 2024	Jul 12, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000422.3:c.275A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000413.1:p.Asn92Ser	missense
NC_000017.11:g.41624235T>C
NC_000017.10:g.39780487T>C
NG_008625.1:g.5396A>G
NG_009090.2:g.167478A>G
LRG_1345:g.5396A>G
LRG_1345t1:c.275A>G	LRG_1345p1:p.Asn92Ser
LRG_401:g.167478A>G
	Q04695:p.Asn92Ser

... more HGVS ... less HGVS

Protein change

N92S

Other names

Canonical SPDI

NC_000017.11:41624234:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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

ClinGen: CA216610 UniProtKB: Q04695#VAR_003849 OMIM: 148069.0002 dbSNP: rs59151893 VarSome

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
Gene	OMIM	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	128	135

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.
Pachyonychia congenita 2	Pathogenic (3)	criteria provided, single submitter	Jul 12, 2022	RCV000015689.39
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 5, 2021	RCV000056512.15
Abnormality of the skin	Pathogenic (1)	criteria provided, single submitter	Jul 10, 2021	RCV001836709.9
Pachyonychia congenita 2 Steatocystoma multiplex	Pathogenic (1)	criteria provided, single submitter	Dec 23, 2021	RCV002496373.8

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 (Jul 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pachyonychia congenita 2 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581056.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS4, PM1, PM5, PM2_SUP, PP1, PP3	Number of individuals with the variant: 1 Sex: female
Pathogenic (Dec 23, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pachyonychia congenita 2 Steatocystoma multiplex Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002811638.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Jul 26, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321826.5 First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016	Comment: The N92S missense variant in the KRT17 gene has been reported previously in association with pachyonychia congenita (Smith et al., 1997; Covello et al., 1998; … (more) The N92S missense variant in the KRT17 gene has been reported previously in association with pachyonychia congenita (Smith et al., 1997; Covello et al., 1998; Ofaiche et al., 2014). N92S is the most common hot spot pathogenic variant in the KRT17 gene associated with pachyonychia congenita or steatocystoma multiplex (Human Intermediate Filament Database). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs within a known mutational hotspot region (helix initiation motif) that is highly conserved across all species and among all members of the keratin family. Many other pathogenic variants in patients with pachyonychia congenita have been reported in the same residue (N92H/D) and in nearby residues (M88T/R, L91P, R94C/S/G/P/H, L95Q/P) according to the Human Gene Mutation Database (Stenson et al., 2014). It is well established that keratin gene mutations 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 hyperkeratosis (Chamcheu et al., 2011). Therefore, we consider N92S to be pathogenic. (less)
Pathogenic (Jul 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormality of the skin Affected status: yes Allele origin: de novo	Kariminejad - Najmabadi Pathology & Genetics Center Accession: SCV000927085.2 First in ClinVar: Jul 24, 2019 Last updated: Feb 20, 2022
Pathogenic (Sep 05, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002231924.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 22336949‚ 31823354 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: 14587). This missense change has been observed in individuals with pachyonychia congenita (PMID: 22336949, 31823354). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with serine at codon 92 of the KRT17 protein (p.Asn92Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. (less)
Pathogenic (Sep 01, 1998)	no assertion criteria provided Method: literature only	PACHYONYCHIA CONGENITA 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035954.3 First in ClinVar: Apr 04, 2013 Last updated: Jun 29, 2024	Publications: PubMed (3) PubMed: 9008238‚ 2248894‚ 9767294 Comment on evidence: In a family in which 5 individuals in 3 generations had pachyonychia congenita described as the Jackson-Lawler type (PC2; 167210), Smith et al. (1997) found … (more) In a family in which 5 individuals in 3 generations had pachyonychia congenita described as the Jackson-Lawler type (PC2; 167210), Smith et al. (1997) found an A-to-G transition in the KRT17 gene, producing a predicted asn92-to-ser (N92S) substitution. The identical mutation was found in 3 sporadic cases. The mutation created a new DdelI site. In affected members of a 3-generation British Caucasian family with PC2, originally described by Todd et al. (1990) as having pachyonychia with hidradenitis suppurativa, Covello et al. (1998) identified heterozygosity for the N92S mutation in the KRT17 gene. (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: SCV000087623.1 First in ClinVar: Oct 19, 2013 Last updated: Oct 19, 2013
not provided (-)	no classification provided Method: literature only	Pachyonychia congenita 2 Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000172481.3 First in ClinVar: Jul 25, 2014 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1280 BookShelf: NBK1280

Comment:

The N92S missense variant in the KRT17 gene has been reported previously in association with pachyonychia congenita (Smith et al., 1997; Covello et al., 1998; Ofaiche et al., 2014). N92S is the most common hot spot pathogenic variant in the KRT17 gene associated with pachyonychia congenita or steatocystoma multiplex (Human Intermediate Filament Database). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs within a known mutational hotspot region (helix initiation motif) that is highly conserved across all species and among all members of the keratin family. Many other pathogenic variants in patients with pachyonychia congenita have been reported in the same residue (N92H/D) and in nearby residues (M88T/R, L91P, R94C/S/G/P/H, L95Q/P) according to the Human Gene Mutation Database (Stenson et al., 2014). It is well established that keratin gene mutations 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 hyperkeratosis (Chamcheu et al., 2011). Therefore, we consider N92S to be pathogenic.

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, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 14587). This missense change has been observed in individuals with pachyonychia congenita (PMID: 22336949, 31823354). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with serine at codon 92 of the KRT17 protein (p.Asn92Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Revisiting pachyonychia congenita: a case-cohort study of 815 patients.	Samuelov L	The British journal of dermatology	2020	PMID: 31823354
Pachyonychia Congenita.	Adam MP	-	2017	PMID: 20301457
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 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
Pachyonychia congenita complicated by hidradenitis suppurativa: a family study.	Todd P	The British journal of dermatology	1990	PMID: 2248894

Text-mined citations for rs59151893 ...

These 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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000422.3(KRT17):c.275A>G (p.Asn92Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs59151893 ...