ClinVar Genomic variation as it relates to human health
NM_000424.4(KRT5):c.74C>T (p.Pro25Leu)
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.74C>T (p.Pro25Leu)
Variation ID: 14648 Accession: VCV000014648.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q13.13 12: 52520223 (GRCh38) [ NCBI UCSC ] 12: 52914007 (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 May 3, 2013 Jun 9, 2024 Feb 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000424.4:c.74C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000415.2:p.Pro25Leu missense NC_000012.12:g.52520223G>A NC_000012.11:g.52914007G>A NG_008297.1:g.5237C>T P13647:p.Pro25Leu - Protein change
- P25L
- Other names
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- Canonical SPDI
- NC_000012.12:52520222:G:A
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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 |
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
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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 (2) |
no assertion criteria provided
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Nov 1, 2010 | RCV000015754.28 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 10, 2024 | RCV000056643.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 26, 2018 | RCV001352721.1 | |
KRT5-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Feb 8, 2024 | RCV003415710.5 |
Submissions - Germline
Classification
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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
(Feb 26, 2018)
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criteria provided, single submitter
Method: research
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Simplex epidermolysis bullosa
Affected status: yes
Allele origin:
de novo,
germline
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Biomedical Innovation Departament, CIEMAT
Accession: SCV001547398.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 3
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Pathogenic
(Feb 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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KRT5-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004109576.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
The KRT5 c.74C>T variant is predicted to result in the amino acid substitution p.Pro25Leu. This variant has been reported in individuals with epidermolysis bullosa simplex … (more)
The KRT5 c.74C>T variant is predicted to result in the amino acid substitution p.Pro25Leu. This variant has been reported in individuals with epidermolysis bullosa simplex (EBS) and the affected family members (see for example, Uttam et al. 1996. PubMed ID: 8799157, reported as P24L; Pascucci et al. 2006. PubMed ID: 17229601; Pfendner et al. 2005. PubMed ID: 16098032; Mariath et al. 2019. PubMed ID: 31001817). This variant has been also reported as de novo in an individual with EBS (Table S1, Chen et al. 2023. PubMed ID: 36287101). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Sep 04, 2020)
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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: SCV001813265.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Published functional studies demonstrate that although P25L does not interfere with alignment and assembly of keratin intermediate filaments, it affects the length and uniformity of … (more)
Published functional studies demonstrate that although P25L does not interfere with alignment and assembly of keratin intermediate filaments, it affects the length and uniformity of the resulting filaments, thus explaining the milder blistering phenotype of EBS-MP (Uttam et al., 1996); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect, although this variant resides within the non-helical variable head domain (V1 region) of keratin 5, which is outside the typical keratin hot spots; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31001817, 30690752, 16581562, 22640275, 21623745, 21375516, 20199538, 20923750, 8799157, 16882168, 16098032, 15827748, 11167681, 10494094, 9129237, 26286811, 15030360, 24964947, 22161089, 23889190, 17229601) (less)
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Pathogenic
(Jan 10, 2024)
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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: SCV004294175.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 25 of the KRT5 protein (p.Pro25Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 25 of the KRT5 protein (p.Pro25Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant epidermolysis bullosa simplex (PMID: 8799157, 15030360, 16098032, 16581562, 17229601). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Pro24Leu. ClinVar contains an entry for this variant (Variation ID: 14648). 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 not expected to disrupt KRT5 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 01, 2010)
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no assertion criteria provided
Method: literature only
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EPIDERMOLYSIS BULLOSA SIMPLEX 2F, WITH MOTTLED PIGMENTATION
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036019.8
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
In 2 unrelated families with epidermolysis bullosa simplex with mottled pigmentation (EBS2F; 131960), one of which had been described originally by Fischer and Gedde-Dahl (1979), … (more)
In 2 unrelated families with epidermolysis bullosa simplex with mottled pigmentation (EBS2F; 131960), one of which had been described originally by Fischer and Gedde-Dahl (1979), Uttam et al. (1996) found a heterozygous C-to-T transition at base position 71 of the KRT5 gene, causing a P24L substitution. The mutation occurred in the V1 domain of keratin 5; previous mutations of K5 or K14 (148066) reported in EBS had been located in the central helical rod domains, with a tendency to aggregate at the highly conserved helix boundary peptides or at the nonhelical L12 linker domain. Irvine et al. (1997) identified the same mutation in the sporadic case of a 6-year-old boy who showed acral blistering, mottled pigmentation of the limbs, and punctate hyperkeratoses primarily affecting the soles. The authors speculated that recurrence of this mutation may be related to the fact that it occurred in a CpG site. Although the mutation might explain the epidermolysis, the cause of the mottled pigmentation remained obscure. Moog et al. (1999) noted that, at the time of their report, the P24L mutation of the KRT5 gene was the only mutation identified in patients with EBS-MP. Moog et al. (1999) described a sporadic patient and a family with an affected 6-year-old girl, her mother, and maternal aunt; all of them had the P24L mutation. The 6-year-old girl showed erythema with telangiectasia on the cheeks and above the upper lip at birth. From 6 months of age, blisters arose daily after minor trauma, predominantly on the distal extremities. The lesions healed without scarring. Over time, the tendency to blistering decreased considerably. However, her skin remained fragile on sites where adhesive tape was used. Hyperpigmented spots that were not preceded by blistering developed from infancy. The mother had mild blistering (always confined to the feet) and mottled pigmentation from infancy. Irvine et al. (2001) reported the KRT5 pro25-to-leu mutation in 2 additional families, both originally described by Boss et al. (1981), increasing the total number of EBS-MP kindreds with this mutation to 7. This mutation was previously reported as PRO24LEU based on the numbering suggested by Lersch et al. (1989), which ignores the initial methionine. All other KRT5 mutations are numbered according to GenBank M21389, which includes methionine. Irvine et al. (2001) suggested that the P25L designation be used in future reports. In a Mexican father, his 5 affected children, and a Finnish woman who all exhibited EBS with mottled pigmentation, Shurman et al. (2006) identified heterozygosity for the recurrent P25L mutation in the KRT5 gene. The authors noted that these were the first reported EBSMP patients of Hispanic or Finnish origin, and stated that this strongly refuted a founder effect for this mutation in EBSMP. Glasz-Bona et al. (2010) identified a heterozygous P25L mutation in affected members of a 4-generation Hungarian pedigree with EBS-MP. There were 10 affected members, 5 of whom were deceased. All had localized blistering and skin fragility in childhood, followed by the development of brownish, lentigo-like mottled pigmentation and hypopigmentation on the trunk and/or extremities in adolescence and adulthood. Two patients also had nail dystrophy. In this family, the P25L mutation segregated with a gly138-to-glu (G138E) polymorphism. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Epidermolysis bullosa simplex with mottled pigmentation
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000040664.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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: SCV000087756.1
First in ClinVar: Oct 19, 2013 Last updated: Oct 19, 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. | Adam MP | - | 2022 | PMID: 20301543 |
Epidermolysis bullosa simplex with mottled pigmentation - mutation analysis proved the diagnosis in a four-generation pedigree. | Glàsz-Bóna A | European journal of dermatology : EJD | 2010 | PMID: 20923750 |
Novel human pathological mutations. Gene symbol: COL7A1. Disease: Epidermolysis bullosa dystrophica. | Escámez MJ | Human genetics | 2010 | PMID: 20108434 |
Epidermolysis Bullosa Simplex with mottled pigmentation: mutation analysis in the first reported Hispanic pedigree with the largest single generation of affected individuals to date. | Shurman D | European journal of dermatology : EJD | 2006 | PMID: 16581562 |
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 |
The P25L mutation in the KRT5 gene in a Japanese family with epidermolysis bullosa simplex with mottled pigmentation. | Hamada T | The British journal of dermatology | 2004 | PMID: 15030360 |
Molecular confirmation of the unique phenotype of epidermolysis bullosa simplex with mottled pigmentation. | Irvine AD | The British journal of dermatology | 2001 | PMID: 11167681 |
Epidermolysis bullosa simplex with mottled pigmentation: clinical aspects and confirmation of the P24L mutation in the KRT5 gene in further patients. | Moog U | American journal of medical genetics | 1999 | PMID: 10494094 |
A mutation in the V1 domain of keratin 5 causes epidermolysis bullosa simplex with mottled pigmentation. | Irvine AD | The Journal of investigative dermatology | 1997 | PMID: 9129237 |
The genetic basis of epidermolysis bullosa simplex with mottled pigmentation. | Uttam J | Proceedings of the National Academy of Sciences of the United States of America | 1996 | PMID: 8799157 |
Isolation, sequence, and expression of a human keratin K5 gene: transcriptional regulation of keratins and insights into pairwise control. | Lersch R | Molecular and cellular biology | 1989 | PMID: 2476664 |
Speckled hyperpigmentation, palmo-plantar punctate keratoses and childhood blistering: a clinical triad, with variable associations. A report of two families. | Boss JM | The British journal of dermatology | 1981 | PMID: 6457621 |
Epidermolysis bullosa simplex and mottled pigmentation: a new dominant syndrome. I. Clinical and histological features. | Fischer T | Clinical genetics | 1979 | PMID: 421361 |
The adult learner in nursing: a program of continuing education in a hospital based school of nursing. | Poteet GW | NLN publications | 1976 | PMID: 1049409 |
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Text-mined citations for rs57499817 ...
HelpRecord last updated Jun 10, 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.