NM_000526.5(KRT14):c.373C>T (p.Arg125Cys) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 21, 2024
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:: RCV000056717.10

Allele description [Variation Report for NM_000526.5(KRT14):c.373C>T (p.Arg125Cys)]

NM_000526.5(KRT14):c.373C>T (p.Arg125Cys)

Gene:

KRT14:keratin 14 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.2

Genomic location:

Preferred name:

NM_000526.5(KRT14):c.373C>T (p.Arg125Cys)

HGVS:

NC_000017.11:g.41586462G>A
NG_008624.1:g.5434C>T
NM_000526.5:c.373C>TMANE SELECT
NP_000517.3:p.Arg125Cys
NC_000017.10:g.39742714G>A
NM_000526.4:c.373C>T
P02533:p.Arg125Cys

Protein change:

R125C; ARG125CYS

Links:

UniProtKB: P02533#VAR_003837; OMIM: 148066.0002; dbSNP: rs60399023

NCBI 1000 Genomes Browser:

rs60399023

Molecular consequence:

NM_000526.5:c.373C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000087830	Epithelial Biology; Institute of Medical Biology, Singapore	no classification provided	not provided	not provided	not provided
SCV000321815	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 11, 2022)	germline	clinical testing	Citation Link,
SCV003441915	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 21, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16098032, 1717157, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000087830

Epithelial Biology; Institute of Medical Biology, Singapore

no classification provided

not provided

SCV000321815

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Apr 11, 2022)

germline

clinical testing

Citation Link,

SCV003441915

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 21, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

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, Sadowski SG, Uitto J.

J Invest Dermatol. 2005 Aug;125(2):239-43.

PubMed [citation]

PMID:: 16098032

Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analyses.

Coulombe PA, Hutton ME, Letai A, Hebert A, Paller AS, Fuchs E.

Cell. 1991 Sep 20;66(6):1301-11.

PubMed [citation]

PMID:: 1717157

See all PubMed Citations (3)

Details of each submission

From Epithelial Biology; Institute of Medical Biology, Singapore, SCV000087830.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	not provided	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV000321815.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Published functional studies demonstrate that this variant results in destabilization of the keratin filament network in basal keratinocytes and may result in intracellular keratin aggregates (Coulombe et al., 1991; Loffek et al., 2010); Located in the helix initiation motif of the 1A domain, a region intolerant to change; keratin gene variants 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); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20301543, 11480251, 10583131, 11331879, 21967011, 20151404, 27065010, 7561171, 10733662, 11869205, 26432462, 28830826, 25326635, 19040520, 16098032, 14962092, 30011071, 31001817, 31772641, 32383240, 33274474, 35052793, 35191026, 31957133, 32616561, 1717157, 26707537, 32484238, 21176769, 19854623)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003441915.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 125 of the KRT14 protein (p.Arg125Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epidermolysis bullosa simplex (PMID: 16098032). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 14612). 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 KRT14 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects KRT14 function (PMID: 1717157). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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