ClinVar Genomic variation as it relates to human health
NM_000423.3(KRT2):c.1459G>A (p.Glu487Lys)
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_000423.3(KRT2):c.1459G>A (p.Glu487Lys)
Variation ID: 9310 Accession: VCV000009310.6
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q13.13 12: 52646750 (GRCh38) [ NCBI UCSC ] 12: 53040534 (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 Mar 14, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000423.3:c.1459G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000414.2:p.Glu487Lys missense NC_000012.12:g.52646750C>T NC_000012.11:g.53040534C>T NG_008296.1:g.10426G>A P35908:p.Glu487Lys - Protein change
- E487K
- Other names
- E493K
- Canonical SPDI
- NC_000012.12:52646749: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.
-
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. |
|||
KRT2 | - | - |
GRCh38 GRCh37 |
173 | 182 |
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
|
May 4, 2022 | RCV000009894.4 | |
Pathogenic (1) |
no assertion criteria provided
|
Apr 1, 1999 | RCV000009895.3 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 14, 2023 | RCV000056532.6 |
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
(Dec 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001766427.2
First in ClinVar: Aug 07, 2021 Last updated: Dec 11, 2022 |
Comment:
Located within the highly conserved helix termination motif (2B) of the rod domain of keratin 2, a well-known mutational hot spot region that is intolerant … (more)
Located within the highly conserved helix termination motif (2B) of the rod domain of keratin 2, a well-known mutational hot spot region that is intolerant to change; Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29171394, 29444371, 26581228, 10688369, 10233323, 31953843, 33081034, 32881395, 7524919, 24077912) (less)
|
|
Pathogenic
(Mar 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004294176.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. 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 KRT2 protein function. ClinVar contains an entry for this variant (Variation ID: 9310). This missense change has been observed in individuals with epidermolytic ichthyosis (PMID: 26581228, 29444371, 31953843). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 487 of the KRT2 protein (p.Glu487Lys). (less)
|
|
Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Ichthyosis bullosa of Siemens
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002516638.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
Pathogenic
(Apr 01, 1999)
|
no assertion criteria provided
Method: literature only
|
ICHTHYOSIS BULLOSA OF SIEMENS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000030115.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 04, 2015 |
Comment on evidence:
In 4 families with autosomal dominant inheritance of ichthyosis bullosa of Siemens (146800) and in 1 sporadic case of this disorder, Rothnagel et al. (1994) … (more)
In 4 families with autosomal dominant inheritance of ichthyosis bullosa of Siemens (146800) and in 1 sporadic case of this disorder, Rothnagel et al. (1994) found a G-to-A transition at nucleotide 1510 resulting in a lysine for glutamic acid substitution at residue 117 of the KRT2 protein. Thus in a total of 6 instances, the mutation occurred in the same codon, GAG (glu); the mutation was to GAT in 1 family and to AAG in the 5 others. (According to Rothnagel et al. (1994), the residue designated 117 corresponds to codon 493 of the published sequence.) In 2 unrelated British families with ichthyosis bullosa of Siemens, McLean et al. (1994) found a glu493-to-lys mutation in the highly conserved LLEGEE helix termination motif, producing a change to LLEGKE. The mutation was predicted to be highly detrimental to keratin filament assembly and/or functional integrity. A G-to-A transition at nucleotide 1510 of the cDNA sequence occurred in a CpG dinucleotide. Kremer et al. (1994) identified the E493K mutation in a family described as having ichthyosis exfoliativa (see 146800), originally reported by Vakilzadeh and Kolde (1991), and in yet another Dutch family with ichthyosis bullosa of Siemens. In a large family with ichthyosis bullosa of Siemens in 8 members spanning 3 generations, Basarab et al. (1999) identified the E493K mutation in the KRT2 gene. The patients showed blistering, superficial peeling of the skin, and localized lichenified hyperkeratosis, mainly confined to the limbs. Phenotypic variation with some individuals exhibiting unusual clinical features was also observed. The index patient was erythrodermic at birth and subsequently developed a widespread pustular eruption. She also had hypertrichosis of the limbs, as did an affected female first cousin. Basarab et al. (1999) found that E493K is by far the most frequent mutation in this disorder. (less)
|
|
Pathogenic
(Apr 01, 1999)
|
no assertion criteria provided
Method: literature only
|
ICHTHYOSIS EXFOLIATIVA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000030116.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 04, 2015 |
Comment on evidence:
In 4 families with autosomal dominant inheritance of ichthyosis bullosa of Siemens (146800) and in 1 sporadic case of this disorder, Rothnagel et al. (1994) … (more)
In 4 families with autosomal dominant inheritance of ichthyosis bullosa of Siemens (146800) and in 1 sporadic case of this disorder, Rothnagel et al. (1994) found a G-to-A transition at nucleotide 1510 resulting in a lysine for glutamic acid substitution at residue 117 of the KRT2 protein. Thus in a total of 6 instances, the mutation occurred in the same codon, GAG (glu); the mutation was to GAT in 1 family and to AAG in the 5 others. (According to Rothnagel et al. (1994), the residue designated 117 corresponds to codon 493 of the published sequence.) In 2 unrelated British families with ichthyosis bullosa of Siemens, McLean et al. (1994) found a glu493-to-lys mutation in the highly conserved LLEGEE helix termination motif, producing a change to LLEGKE. The mutation was predicted to be highly detrimental to keratin filament assembly and/or functional integrity. A G-to-A transition at nucleotide 1510 of the cDNA sequence occurred in a CpG dinucleotide. Kremer et al. (1994) identified the E493K mutation in a family described as having ichthyosis exfoliativa (see 146800), originally reported by Vakilzadeh and Kolde (1991), and in yet another Dutch family with ichthyosis bullosa of Siemens. In a large family with ichthyosis bullosa of Siemens in 8 members spanning 3 generations, Basarab et al. (1999) identified the E493K mutation in the KRT2 gene. The patients showed blistering, superficial peeling of the skin, and localized lichenified hyperkeratosis, mainly confined to the limbs. Phenotypic variation with some individuals exhibiting unusual clinical features was also observed. The index patient was erythrodermic at birth and subsequently developed a widespread pustular eruption. She also had hypertrichosis of the limbs, as did an affected female first cousin. Basarab et al. (1999) found that E493K is by far the most frequent mutation in this disorder. (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: SCV000087643.1
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 |
---|---|---|---|---|
Next-generation sequencing through multi-gene panel testing for diagnosis of hereditary ichthyosis in Chinese. | Cheng R | Clinical genetics | 2020 | PMID: 31953843 |
Whole-exome sequencing for diagnosis of hereditary ichthyosis. | Sitek JC | Journal of the European Academy of Dermatology and Venereology : JEADV | 2018 | PMID: 29444371 |
Expanding the Clinical and Genetic Spectrum of KRT1, KRT2 and KRT10 Mutations in Keratinopathic Ichthyosis. | Hotz A | Acta dermato-venereologica | 2016 | PMID: 26581228 |
Ichthyosis bullosa of Siemens: report of a family with evidence of a keratin 2e mutation, and a review of the literature. | Basarab T | The British journal of dermatology | 1999 | PMID: 10233323 |
Ichthyosis bullosa of Siemens is caused by mutations in the keratin 2e gene. | Kremer H | The Journal of investigative dermatology | 1994 | PMID: 8077693 |
Mutations in the rod domain of keratin 2e in patients with ichthyosis bullosa of Siemens. | Rothnagel JA | Nature genetics | 1994 | PMID: 7524919 |
Ichthyosis bullosa of Siemens--a disease involving keratin 2e. | McLean WH | The Journal of investigative dermatology | 1994 | PMID: 7521371 |
Autosomal dominant ichthyosis exfoliativa. | Vakilzadeh F | The British journal of dermatology | 1991 | PMID: 2004005 |
Text-mined citations for rs137852629 ...
HelpRecord last updated Sep 29, 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.