NM_000421.5(KRT10):c.1345T>C (p.Tyr449His) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jul 1, 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:: RCV001912733.9

Allele description [Variation Report for NM_000421.5(KRT10):c.1345T>C (p.Tyr449His)]

NM_000421.5(KRT10):c.1345T>C (p.Tyr449His)

Genes:

KRT10-AS1:KRT10 antisense RNA 1 [Gene - HGNC]
KRT10:keratin 10 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.2

Genomic location:

Preferred name:

NM_000421.5(KRT10):c.1345T>C (p.Tyr449His)

HGVS:

NC_000017.11:g.40819545A>G
NG_008405.1:g.8067T>C
NM_000421.5:c.1345T>CMANE SELECT
NM_001379366.1:c.1345T>C
NP_000412.4:p.Tyr449His
NP_001366295.1:p.Tyr449His
NC_000017.10:g.38975797A>G

Protein change:

Y449H

Links:

dbSNP: rs2143133897

NCBI 1000 Genomes Browser:

rs2143133897

Molecular consequence:

NM_000421.5:c.1345T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001379366.1:c.1345T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV002176887	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 29, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21271994, 21463361, 31953843, 26581228, 31106763, 28492532
SCV005092633	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Jul 1, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002176887

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 29, 2021)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV005092633

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Likely pathogenic
(Jul 1, 2024)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	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

Citations

PubMed

Expanding the keratin mutation database: novel and recurrent mutations and genotype-phenotype correlations in 28 patients with epidermolytic ichthyosis.

Arin MJ, Oji V, Emmert S, Hausser I, Traupe H, Krieg T, Grimberg G.

Br J Dermatol. 2011 Feb;164(2):442-7. doi: 10.1111/j.1365-2133.2010.10096.x.

PubMed [citation]

PMID:: 21271994

Novel mutation of the KRT 10 gene in a Japanese patient with epidermolytic hyperkeratosis.

Makino T, Furuichi M, Asano Y, Shimizu T.

J Dermatol. 2012 Jan;39(1):87-9. doi: 10.1111/j.1346-8138.2011.01234.x. Epub 2011 Apr 5. No abstract available.

PubMed [citation]

PMID:: 21463361

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002176887.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr449 amino acid residue in KRT10. Other variant(s) that disrupt this residue have been observed in individuals with KRT10-related conditions (PMID: 21271994, 21463361, 31953843), which suggests that this may be a clinically significant amino acid residue. 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 expected to disrupt KRT10 protein function. This variant has been observed in individuals with autosomal dominant epidermolytic ichthyosis (PMID: 26581228, 31106763). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with histidine at codon 449 of the KRT10 protein (p.Tyr449His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine.

#	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

From CeGaT Center for Human Genetics Tuebingen, SCV005092633.3

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

Description

KRT10: PM2, PM5, PS4:Moderate, PP3, PP4

#	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		1	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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