VCV000014612.22 - ClinVar

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

Germline

Classification

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.

(13)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 14612 Accession: VCV000014612.22

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.2 17: 41586462 (GRCh38) [ NCBI UCSC ] 17: 39742714 (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	Apr 4, 2013	Nov 24, 2024	Sep 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000526.5:c.373C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000517.3:p.Arg125Cys	missense
NC_000017.11:g.41586462G>A
NC_000017.10:g.39742714G>A
NG_008624.1:g.5434C>T
	P02533:p.Arg125Cys

... more HGVS ... less HGVS

Protein change

R125C

Other names

Canonical SPDI

NC_000017.11:41586461:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA216919 UniProtKB: P02533#VAR_003837 OMIM: 148066.0002 dbSNP: rs60399023 VarSome

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
Gene	OMIM	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.
KRT14		-	-	GRCh38 GRCh37	231	239

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.
Epidermolysis bullosa simplex 1A, generalized severe	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Sep 19, 2024	RCV000015716.32
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 21, 2024	RCV000056717.10
Epidermolysis bullosa simplex	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 1, 2017	RCV000679886.5
Epidermolysis bullosa simplex, Koebner type	Pathogenic (1)	criteria provided, single submitter	Jan 3, 2022	RCV001807730.2
Epidermolysis bullosa simplex 1A, generalized severe Epidermolysis bullosa simplex, Koebner type	Pathogenic (1)	criteria provided, single submitter	Feb 15, 2022	RCV002243645.3
KRT14-related disorder	Pathogenic (1)	no assertion criteria provided	Aug 22, 2024	RCV003924837.2

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 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 (Oct 13, 2009)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Simplex epidermolysis bullosa Affected status: yes Allele origin: germline, de novo	Biomedical Innovation Departament, CIEMAT Accession: SCV001547420.1 First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021	Publications: PubMed (1) PubMed: 21623745 Observation 1: Number of individuals with the variant: 3 Observation 2: Number of individuals with the variant: 3
Pathogenic (Feb 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Epidermolysis bullosa simplex 1A, generalized severe Epidermolysis bullosa simplex, Koebner type Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002512250.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Comment: ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderate, PM2 moderate, PM5, PM6 moderate, PP1 supporting, PP3 supporting Geographic origin: Brazil
Pathogenic (Sep 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Epidermolysis bullosa simplex (Autosomal unknown) Affected status: yes Allele origin: de novo	Baylor Genetics Accession: SCV000807285.2 First in ClinVar: Sep 17, 2018 Last updated: Dec 11, 2022	Publications: PubMed (2) PubMed: 25326635‚ 20151404 Comment: This mutation has been previously reported as disease-causing and was found once in our laboratory de novo in a 9-month-old male with epidrmolysis bullosa simplex … (more) This mutation has been previously reported as disease-causing and was found once in our laboratory de novo in a 9-month-old male with epidrmolysis bullosa simplex in wrist, hands, feet, and mouth; preauricular skin tag, microcephalic, normal development (less)
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Epidermolysis bullosa simplex, Koebner type Affected status: yes Allele origin: germline	3billion Accession: SCV002058617.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:1717157 PMID:1717157 Comment: Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014612, PMID:1717157, PS1_S). Different … (more) Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014612, PMID:1717157, PS1_S). Different missense changes at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014613, PMID:1717157, 7561171, 12890194, 14987259, 19854623, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.899, 3CNET: 0.991, PP3_P). A missense variant is a common mechanism associated with Epidermolysis bullosa simplex 1B (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Abnormal nail morphology (present) , Milia (present) , Abnormal blistering of the skin (present) , Skin erosion (present)
Pathogenic (Apr 11, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321815.11 First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Jan 21, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003441915.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 16098032‚ 1717157 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 29, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Epidermolysis bullosa simplex 1A, generalized severe Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004807673.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Pathogenic (Sep 19, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Epidermolysis bullosa simplex 1A, generalized severe (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005398004.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (2) PubMed: 16960809‚ 18717745 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene. Autosomal dominant epidermolysis bullosa simplex (EBS) is caused by dominant negative missense variants located in the central alpha-helical rod domain. Autosomal recessive EBS is caused by loss of function variants affecting more central or distal regions of the protein. Autosomal dominant Naegeli-Franceschetti-Jadassohn syndrome is caused by haploinsufficiency due to N-terminal (E1/V1 domain) null variants (PMID: 16960809). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. It is located at the start of the 1A segment of the rod domain (PMID: 18717745), which is one of the clusters of pathogenic variants associated with severe EBS (GeneReviews). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is regarded as pathogenic by multiple diagnostic laboratories in ClinVar and is one of the most common pathogenic variants associated with severe EBS (GeneReviews; PMID: 18717745). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (May 01, 2001)	no assertion criteria provided Method: literature only	EPIDERMOLYSIS BULLOSA SIMPLEX 1A, GENERALIZED SEVERE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035981.5 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024	Publications: PubMed (6) PubMed: 1717157‚ 10583131‚ 10733662‚ 11331879‚ 26743602‚ 31957133 Comment on evidence: Epidermolysis bullosa simplex, severe type (EBS1A; 131760), formerly known as the Dowling-Meara type, is distinguished from other subtypes not only by its severity but also … (more) Epidermolysis bullosa simplex, severe type (EBS1A; 131760), formerly known as the Dowling-Meara type, is distinguished from other subtypes not only by its severity but also by the presence of large cytoplasmic clumps of tonofilaments that can be labeled with antibodies against the basal epidermal keratins. In 2 patients with the Dowling-Meara form, Coulombe et al. (1991) demonstrated critical mutations in the KRT14 gene. One patient had a C-to-T transition corresponding to nucleotide 433 of the gene, converting an arginine residue (CGC) to a cysteine residue (TGC) at amino acid 125 (R125C), located near the amino end of the KRT14 rod segment. To demonstrate the effect on function, Coulombe et al. (1991) engineered the arg125-to-cys mutation in a KRT14 cDNA and showed that this cDNA disrupted keratin network formation in transfected keratinocytes and disturbed filament assembly in vitro. Also see 148066.0003. Sasaki et al. (1999) reported that the arg125-to-cys mutation had been identified in 4 of 6 Japanese families with the Dowling-Meara type of EBS. They stated that 8 of 19 families with mutations in the KRT14 gene carried the arg125-to-cys mutation. Hut et al. (2000) identified a de novo heterozygous R125C mutation in 2 patients with EBS Dowling-Meara type. Ma et al. (2001) used differential interference contrast microscopy to show that the arg125-to-cys mutation in the KRT14 gene greatly reduced the ability of reconstituted mutant filaments to bundle under crosslinking conditions, possibly causing the fragility of epithelial cells seen in some keratin-based disorders. From a cohort of 33 newborns with generalized severe EBS who were reported to the National Health Service of the UK over a 15-year period and underwent genetic analysis, Sathishkumar et al. (2016) identified 2 patients who were heterozygous for the R125C mutation in the KRT14 gene. In an Italian male infant with generalized severe EB simplex and a hoarse cry with mild inspiratory stridor, Diociaiuti et al. (2020) identified heterozygosity for the recurrent R125C mutation in the KRT14 gene. The mutation arose de novo in the proband. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Epidermolysis bullosa simplex 1A, generalized severe (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Narges Medical Genetic and Prenatal Diagnosis Lab Accession: SCV004035030.1 First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023	Sex: female
Pathogenic (Aug 22, 2024)	no assertion criteria provided Method: clinical testing	KRT14-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004743720.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The KRT14 c.373C>T variant is predicted to result in the amino acid substitution p.Arg125Cys. This variant has been reported in many individuals with epidermolysis bullosa … (more) The KRT14 c.373C>T variant is predicted to result in the amino acid substitution p.Arg125Cys. This variant has been reported in many individuals with epidermolysis bullosa simplex, including several in whom the variant occurred de novo (see, for example, Coulombe et al. 1991. PubMed ID: 1717157; Pfendner et al. 2005. PubMed ID: 16098032; Table S1, Chen et al. 2023. PubMed ID: 36287101). Functional studies support its pathogenicity (Coulombe et al. 1991. PubMed ID: 1717157; Fujiwara et al. 2020. PubMed ID: 32616561). Alternative nucleotide changes affecting the same amino acid (p.Arg125His, p.Arg125Ser, p.Arg125Gly, p.Arg125Pro, p.Arg125Leu) have been reported in individuals with epidermolysis bullosa simplex (Coulombe et al. 1991. PubMed ID: 1717157; Chen et al. 2023. PubMed ID: 36287101; Csikos et al. 2004. PubMed ID: 14987259; Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php). The c.373C>T (p.Arg125Cys) variant has not been reported in a large population database, indicating it is rare. In summary, this variant is interpreted as pathogenic. (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: SCV000087830.1 First in ClinVar: Oct 19, 2013 Last updated: Oct 19, 2013
not provided (-)	no classification provided Method: literature only	Epidermolysis bullosa simplex 1A, generalized severe Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000040749.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (4) PubMed: 10583131‚ 11331879‚ 1717157‚ 20301543 BookShelf: NBK1369 BookShelf: NBK1369
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Comment:

This mutation has been previously reported as disease-causing and was found once in our laboratory de novo in a 9-month-old male with epidrmolysis bullosa simplex in wrist, hands, feet, and mouth; preauricular skin tag, microcephalic, normal development

Comment:

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014612, PMID:1717157, PS1_S). Different missense changes at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014613, PMID:1717157, 7561171, 12890194, 14987259, 19854623, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.899, 3CNET: 0.991, PP3_P). A missense variant is a common mechanism associated with Epidermolysis bullosa simplex 1B (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

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)

Comment:

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.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene. Autosomal dominant epidermolysis bullosa simplex (EBS) is caused by dominant negative missense variants located in the central alpha-helical rod domain. Autosomal recessive EBS is caused by loss of function variants affecting more central or distal regions of the protein. Autosomal dominant Naegeli-Franceschetti-Jadassohn syndrome is caused by haploinsufficiency due to N-terminal (E1/V1 domain) null variants (PMID: 16960809). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. It is located at the start of the 1A segment of the rod domain (PMID: 18717745), which is one of the clusters of pathogenic variants associated with severe EBS (GeneReviews). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is regarded as pathogenic by multiple diagnostic laboratories in ClinVar and is one of the most common pathogenic variants associated with severe EBS (GeneReviews; PMID: 18717745). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

The KRT14 c.373C>T variant is predicted to result in the amino acid substitution p.Arg125Cys. This variant has been reported in many individuals with epidermolysis bullosa simplex, including several in whom the variant occurred de novo (see, for example, Coulombe et al. 1991. PubMed ID: 1717157; Pfendner et al. 2005. PubMed ID: 16098032; Table S1, Chen et al. 2023. PubMed ID: 36287101). Functional studies support its pathogenicity (Coulombe et al. 1991. PubMed ID: 1717157; Fujiwara et al. 2020. PubMed ID: 32616561). Alternative nucleotide changes affecting the same amino acid (p.Arg125His, p.Arg125Ser, p.Arg125Gly, p.Arg125Pro, p.Arg125Leu) have been reported in individuals with epidermolysis bullosa simplex (Coulombe et al. 1991. PubMed ID: 1717157; Chen et al. 2023. PubMed ID: 36287101; Csikos et al. 2004. PubMed ID: 14987259; Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php). The c.373C>T (p.Arg125Cys) variant has not been reported in a large population database, indicating it is rare. In summary, this variant is interpreted as pathogenic.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Epidermolysis Bullosa Simplex.	Adam MP	-	2022	PMID: 20301543
Hoarse cry in a newborn with epidermolysis bullosa simplex, generalized severe.	Diociaiuti A	Pediatric dermatology	2020	PMID: 31957133
The p.Glu477Lys Mutation in Keratin 5 Is Strongly Associated with Mortality in Generalized Severe Epidermolysis Bullosa Simplex.	Sathishkumar D	The Journal of investigative dermatology	2016	PMID: 26743602
Two novel recessive mutations in KRT14 identified in a cohort of 21 Spanish families with epidermolysis bullosa simplex.	García M	The British journal of dermatology	2011	PMID: 21623745
The ubiquitin ligase CHIP/STUB1 targets mutant keratins for degradation.	Löffek S	Human mutation	2010	PMID: 20151404
A recurrent keratin 14 mutation in Dowling-Meara epidermolysis bullosa simplex in a Chinese family.	Wu JW	Journal of the European Academy of Dermatology and Venereology : JEADV	2009	PMID: 18717745
Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal dysplasias caused by dominant mutations in KRT14.	Lugassy J	American journal of human genetics	2006	PMID: 16960809
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 'hot-spot' mutation alters the mechanical properties of keratin filament networks.	Ma L	Nature cell biology	2001	PMID: 11331879
Exempting homologous pseudogene sequences from polymerase chain reaction amplification allows genomic keratin 14 hotspot mutation analysis.	Hut PH	The Journal of investigative dermatology	2000	PMID: 10733662
A recurrent keratin 14 mutation in Dowling-Meara epidermolysis bullosa simplex.	Sasaki Y	The British journal of dermatology	1999	PMID: 10583131
Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analyses.	Coulombe PA	Cell	1991	PMID: 1717157
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Text-mined citations for rs60399023 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs60399023 ...