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NM_000424.4(KRT5):c.1649del (p.Gly550fs) AND not provided

Germline classification:
Pathogenic (4 submissions)
Last evaluated:
Oct 23, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000056578.8

Allele description [Variation Report for NM_000424.4(KRT5):c.1649del (p.Gly550fs)]

NM_000424.4(KRT5):c.1649del (p.Gly550fs)

Gene:
KRT5:keratin 5 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
12q13.13
Genomic location:
Preferred name:
NM_000424.4(KRT5):c.1649del (p.Gly550fs)
HGVS:
  • NC_000012.12:g.52515071del
  • NG_008297.1:g.10394del
  • NM_000424.4:c.1649delMANE SELECT
  • NP_000415.2:p.Gly550fs
  • NC_000012.11:g.52908850del
  • NC_000012.11:g.52908855del
  • NM_000424.3:c.1649del
  • NM_000424.3:c.1649delG
  • NM_000424.4:c.1649delGMANE SELECT
  • p.Gly550Alafs*77
Protein change:
G550fs
Links:
OMIM: 148040.0017; dbSNP: rs61126080
NCBI 1000 Genomes Browser:
rs61126080
Molecular consequence:
  • NM_000424.4:c.1649del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000087691Epithelial Biology; Institute of Medical Biology, Singapore
no classification provided
not providednot providednot provided

SCV000709814GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Pathogenic
(Aug 24, 2020)
germlineclinical testing

Citation Link,

SCV002179518Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Oct 23, 2023)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providednot providednot providednot providednot providednot provided2not providedliterature only

Citations

PubMed

A usual frameshift and delayed termination codon mutation in keratin 5 causes a novel type of epidermolysis bullosa simplex with migratory circinate erythema.

Gu LH, Kim SC, Ichiki Y, Park J, Nagai M, Kitajima Y.

J Invest Dermatol. 2003 Sep;121(3):482-5.

PubMed [citation]
PMID:
12925204

Identification of somatic and germline mosaicism for a keratin 5 mutation in epidermolysis bullosa simplex in a family of which the proband was previously regarded as a sporadic case.

Nagao-Watanabe M, Fukao T, Matsui E, Kaneko H, Inoue R, Kawamoto N, Kasahara K, Nagai M, Ichiki Y, Kitajima Y, Kondo N.

Clin Genet. 2004 Sep;66(3):236-8.

PubMed [citation]
PMID:
15324323
See all PubMed Citations (5)

Details of each submission

From Epithelial Biology; Institute of Medical Biology, Singapore, SCV000087690.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providednot providednot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot provided1not providednot providednot providednot providednot providednot provided

From Epithelial Biology; Institute of Medical Biology, Singapore, SCV000087691.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providednot providednot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot provided1not providednot providednot providednot providednot providednot provided

From GeneDx, SCV000709814.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Frameshift variant predicted to result in protein extension, replacing the last 41 amino acids with an elongated segment of 76 amino acids with different characteristics; Published functional studies demonstrates a damaging effect as in vitro expressed mutant K5 forms much shorter polymers with K14 than wildtype K5 with viscoelastic properties too weak to be reliably measured (Gu et al., 2005); In contrast to the typical hot spot mutations in KRT5 that affect the central rod domain, this variant is predicted to extend the tail domain of keratin 5 and completely alter its composition and physico-chemical properties; the extended tail region has been proposed to interfere with functional interactions between this keratin and its associated proteins (Gu et al., 2005); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20199538, 20055872, 27730678, 24104543, 23993914, 23889190, 15647384, 15982306, 28830826, 15324323, 12925204, 21375516, 32484238, 33274474)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV002179518.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change results in a frameshift in the KRT5 gene (p.Gly550Alafs*77). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the KRT5 protein and extend the protein by 35 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with autosomal dominant epidermolysis bullosa simplex (PMID: 12925204, 15324323, 24104543). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14655). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this frameshift affects KRT5 function (PMID: 15647384). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Flagged submissions

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000087690Epithelial Biology; Institute of Medical Biology, Singapore
flagged submission
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV000087690 appears to be redundant with SCV000087691.
not providednot providednot provided

Last Updated: May 19, 2024