ClinVar Genomic variation as it relates to human health
NM_005557.4(KRT16):c.374A>G (p.Asn125Ser)
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
-
NM_005557.4(KRT16):c.374A>G (p.Asn125Ser)
Variation ID: 14602 Accession: VCV000014602.8
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q21.2 17: 41612315 (GRCh38) [ NCBI UCSC ] 17: 39768567 (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 Feb 14, 2024 Aug 28, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_005557.4:c.374A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005548.2:p.Asn125Ser missense NC_000017.11:g.41612315T>C NC_000017.10:g.39768567T>C NG_008301.1:g.5513A>G P08779:p.Asn125Ser - Protein change
- N125S
- Other names
- -
- Canonical SPDI
- NC_000017.11:41612314:T:C
-
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.
-
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. |
|||
KRT16 | - | - |
GRCh38 GRCh37 |
120 | 127 |
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 (1) |
no assertion criteria provided
|
Oct 1, 2005 | RCV000015706.27 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 28, 2023 | RCV000057037.7 | |
Pathogenic (1) |
no assertion criteria provided
|
Oct 1, 2005 | RCV000144080.3 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000763397.2 |
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
(Apr 13, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321822.7
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
Comment:
Located within a known hotspot region, the helix initiation motif in the 1A domain, which is intolerant to change and highly conserved across all species … (more)
Located within a known hotspot region, the helix initiation motif in the 1A domain, which is intolerant to change and highly conserved across all species and among all members of the keratin family (Chamcheu et al., 2011); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Immunostaining of tooth enamel from a PC patient with the N125S variant showed abnormal K16 protein aggregation and atypical cracks within the inner enamel, and in vitro expression demonstrated altered keratin intermediate filament assembly and intracellular clumping (Duverger et al., 2019); Reported as pathogenic in ClinVar and the KIF database (VCV000014602; Landrum et al., 2016; Szeverenyi et al., 2008); This variant is associated with the following publications: (PMID: 24491404, 8595410, 30009827, 28794556, 30859684, 31021398, 16250206, 21160496, 17719747, 31823354) (less)
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Pachyonychia congenita 1
Palmoplantar keratoderma, nonepidermolytic, focal 1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894119.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447598.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Nail dysplasia (present)
Sex: female
|
|
Pathogenic
(Aug 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002234490.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This variant is also known as N8S. ClinVar contains an entry for this variant (Variation ID: 14602). Advanced modeling of protein sequence and biophysical properties … (more)
This variant is also known as N8S. ClinVar contains an entry for this variant (Variation ID: 14602). 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 KRT16 protein function. This variant disrupts the p.Asn125 amino acid residue in KRT16. Other variant(s) that disrupt this residue have been observed in individuals with KRT16-related conditions (PMID: 22668561), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individuals with pachyonychia congenita (PMID: 8595410, 24491404, 31823354; Invitae). 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 asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 125 of the KRT16 protein (p.Asn125Ser). (less)
|
|
Pathogenic
(Oct 01, 2005)
|
no assertion criteria provided
Method: literature only
|
PACHYONYCHIA CONGENITA 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000189155.2
First in ClinVar: Sep 22, 2014 Last updated: Jun 08, 2015 |
Comment on evidence:
In a father and daughter with focal nonepidermolytic palmoplantar keratoderma (FNEPPK1; 613000), who also had follicular and orogenital hyperkeratosis, Shamsher et al. (1995) identified heterozygosity … (more)
In a father and daughter with focal nonepidermolytic palmoplantar keratoderma (FNEPPK1; 613000), who also had follicular and orogenital hyperkeratosis, Shamsher et al. (1995) identified heterozygosity for an asn125-to-ser (N125S) substitution in the KRT16 gene at a highly conserved residue in the helix initiation motif of the 1A domain. The mutation was not found in 20 controls. An alternative designation for this mutation is N8S. In 2 probands, 1 from a family with pachyonychia congenita (PC1; 167200) and 1 from a family with FNEPPK, Smith et al. (2005) identified heterozygosity for a c.374A-G transition in KRT16, resulting in the N125S substitution. The proband from the family with PC showed typical hypertrophic nail dystrophy in 17 of 20 nails, whereas the proband from the FNEPPK family exhibited no nail thickening and had only minor splinter hemorrhages of the nails. (less)
|
|
Pathogenic
(Oct 01, 2005)
|
no assertion criteria provided
Method: literature only
|
PALMOPLANTAR KERATODERMA, NONEPIDERMOLYTIC, FOCAL 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035971.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 08, 2015 |
Comment on evidence:
In a father and daughter with focal nonepidermolytic palmoplantar keratoderma (FNEPPK1; 613000), who also had follicular and orogenital hyperkeratosis, Shamsher et al. (1995) identified heterozygosity … (more)
In a father and daughter with focal nonepidermolytic palmoplantar keratoderma (FNEPPK1; 613000), who also had follicular and orogenital hyperkeratosis, Shamsher et al. (1995) identified heterozygosity for an asn125-to-ser (N125S) substitution in the KRT16 gene at a highly conserved residue in the helix initiation motif of the 1A domain. The mutation was not found in 20 controls. An alternative designation for this mutation is N8S. In 2 probands, 1 from a family with pachyonychia congenita (PC1; 167200) and 1 from a family with FNEPPK, Smith et al. (2005) identified heterozygosity for a c.374A-G transition in KRT16, resulting in the N125S substitution. The proband from the family with PC showed typical hypertrophic nail dystrophy in 17 of 20 nails, whereas the proband from the FNEPPK family exhibited no nail thickening and had only minor splinter hemorrhages of the nails. (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: SCV000088150.1
First in ClinVar: Oct 19, 2013 Last updated: Oct 19, 2013 |
|
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 |
---|---|---|---|---|
Revisiting pachyonychia congenita: a case-cohort study of 815 patients. | Samuelov L | The British journal of dermatology | 2020 | PMID: 31823354 |
Pachyonychia congenita in Japan: report of familial cases with a recurrent KRT16 mutation. | Inaba Y | European journal of dermatology : EJD | 2014 | PMID: 24491404 |
Two novel de novo mutations of KRT6A and KRT16 genes in two Chinese pachyonychia congenita pedigrees with fissured tongue or diffuse plantar keratoderma. | Du ZF | European journal of dermatology : EJD | 2012 | PMID: 22668561 |
The genetic basis of pachyonychia congenita. | Smith FJ | The journal of investigative dermatology. Symposium proceedings | 2005 | PMID: 16250206 |
Novel mutations in keratin 16 gene underly focal non-epidermolytic palmoplantar keratoderma (NEPPK) in two families. | Shamsher MK | Human molecular genetics | 1995 | PMID: 8595410 |
Text-mined citations for rs60723330 ...
HelpRecord last updated Feb 20, 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.