ClinVar Genomic variation as it relates to human health
NM_000424.4(KRT5):c.1400T>C (p.Ile467Thr)
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
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NM_000424.4(KRT5):c.1400T>C (p.Ile467Thr)
Variation ID: 66210 Accession: VCV000066210.3
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q13.13 12: 52516676 (GRCh38) [ NCBI UCSC ] 12: 52910460 (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 20, 2013 Feb 14, 2024 Jul 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000424.4:c.1400T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000415.2:p.Ile467Thr missense NC_000012.12:g.52516676A>G NC_000012.11:g.52910460A>G NG_008297.1:g.8784T>C P13647:p.Ile467Thr - Protein change
- I467T
- Other names
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- Canonical SPDI
- NC_000012.12:52516675:A:G
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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
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The frequency of the allele represented by this VCV record.
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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
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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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KRT5 | - | - |
GRCh38 GRCh37 |
213 | 328 | |
LOC126861525 | - | - | - | GRCh38 | - | 64 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 18, 2023 | RCV000056556.2 |
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
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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
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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
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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
(Jan 10, 2017)
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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: SCV000568716.4
First in ClinVar: Oct 20, 2013 Last updated: Oct 20, 2013 |
Comment:
The I467T pathogenic variant has been reported previously in association with epidermolysis bullosa simplex (Irvine et al. 1997, Arin et al. 2010). It was not … (more)
The I467T pathogenic variant has been reported previously in association with epidermolysis bullosa simplex (Irvine et al. 1997, Arin et al. 2010). It was not observed in approximately 6500 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 termination motif of the coil 2B region of the protein that is highly conserved across all species and among all members of the keratin family. Many other pathogenic variants in patients with epidermolysis bullosa simplex have been reported in the same residue (I467K, I467L, I467M) and in nearby residues (L463P, E466D, T469P, Y470H, R471C, R471H) 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 skin fragility, blistering and/or hyperkeratosis (Chamcheu et al., 2011). Therefore, I467T is pathogenic and consistent with a diagnosis of epidermolysis bullosa simplex (EBS). (less)
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Pathogenic
(Jul 18, 2023)
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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: SCV004294170.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ile467 amino acid residue in KRT5. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ile467 amino acid residue in KRT5. Other variant(s) that disrupt this residue have been observed in individuals with KRT5-related conditions (PMID: 16098032, 17039244), which suggests that this may be a clinically significant amino acid residue. 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 KRT5 protein function. ClinVar contains an entry for this variant (Variation ID: 66210). This variant is also known as I466T. This missense change has been observed in individual(s) with autosomal dominant epidermolysis bullosa simplex (PMID: 9406827). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 467 of the KRT5 protein (p.Ile467Thr). (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: SCV000087667.1
First in ClinVar: Oct 20, 2013 Last updated: Oct 20, 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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Epidermolysis bullosa simplex in Scotland caused by a spectrum of keratin mutations. | Rugg EL | The Journal of investigative dermatology | 2007 | PMID: 17039244 |
Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis. | Pfendner EG | The Journal of investigative dermatology | 2005 | PMID: 16098032 |
A novel mutation in the helix termination peptide of keratin 5 causing epidermolysis bullosa simplex Dowling-Meara. | Irvine AD | The Journal of investigative dermatology | 1997 | PMID: 9406827 |
Text-mined citations for rs60271599 ...
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.