rs60399023

Variant names:

• chr17-41586462-G-A
• rs60399023
• NM_000526.5:c.373C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-41586462-G-A
• chr17-41586462-G-C
• chr17-41586462-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000526.5(KRT14):​c.373C>T​(p.Arg125Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R125G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT14 NM_000526.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:2
• Conservation: PhyloP100: 9.92

Genes affected

KRT14 (HGNC:6416): (keratin 14) This gene encodes a member of the keratin family, the most diverse group of intermediate filaments. This gene product, a type I keratin, is usually found as a heterotetramer with two keratin 5 molecules, a type II keratin. Together they form the cytoskeleton of epithelial cells. Mutations in the genes for these keratins are associated with epidermolysis bullosa simplex. At least one pseudogene has been identified at 17p12-p11. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a region_of_interest Coil 1A (size 35) in uniprot entity K1C14_HUMAN there are 17 pathogenic changes around while only 1 benign (94%) in NM_000526.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 17-41586462-G-A is Pathogenic according to our data. Variant chr17-41586462-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41586462-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT14	NM_000526.5	c.373C>T	p.Arg125Cys	missense_variant	Exon 1 of 8	ENST00000167586.7	NP_000517.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT14	ENST00000167586.7	c.373C>T	p.Arg125Cys	missense_variant	Exon 1 of 8	1	NM_000526.5	ENSP00000167586.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epidermolysis bullosa simplex 1A, generalized severe Pathogenic:4 Other:1

Sep 19, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

May 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Narges Medical Genetic and Prenatal Diagnosis Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:2 Other:1

Sep 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 11, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Epidermolysis bullosa simplex Pathogenic:2

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Oct 13, 2009

Biomedical Innovation Departament, CIEMAT

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Epidermolysis bullosa simplex 1A, generalized severe;C5561924:Epidermolysis bullosa simplex, Koebner type Pathogenic:1

Feb 15, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderate, PM2 moderate, PM5, PM6 moderate, PP1 supporting, PP3 supporting -

KRT14-related disorder Pathogenic:1

Aug 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Epidermolysis bullosa simplex, Koebner type Pathogenic:1

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.010	D
Polyphen		0.95	P
Vest4		0.99
MutPred		0.98		Gain of catalytic residue at L126 (P = 0.0192);
MVP		0.97
MPC		1.5
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.44
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs60399023; hg19: chr17-39742714;