VCV000066163.3 - ClinVar

NM_000421.5(KRT10):c.1337T>C (p.Ile446Thr)

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.

(3)

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, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000421.5(KRT10):c.1337T>C (p.Ile446Thr)

Variation ID: 66163 Accession: VCV000066163.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.2 17: 40819553 (GRCh38) [ NCBI UCSC ] 17: 38975805 (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	Oct 20, 2013	Jul 23, 2024	Jun 20, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000421.5:c.1337T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000412.4:p.Ile446Thr	missense
NM_001379366.1:c.1337T>C	NP_001366295.1:p.Ile446Thr	missense
NC_000017.11:g.40819553A>G
NC_000017.10:g.38975805A>G
NG_008405.1:g.8059T>C
	P13645:p.Ile446Thr

... more HGVS ... less HGVS

Protein change

I446T

Other names

I107T

Canonical SPDI

NC_000017.11:40819552:A:G

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: CA216572 UniProtKB: P13645#VAR_010511 OMIM: 148080.0028 dbSNP: rs62651994 VarSome

Comment on variant

NCBI staff provided HGVS sequences for OMIM allelic variant 148080.0028 from the sequence reported in Figure 3 of the paper by Suga et al., 1998 (PubMed 9856845).

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.
KRT10		-	-	GRCh38 GRCh37	95	208
KRT10-AS1	-	-	-	GRCh38 GRCh37	21	134

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.
not provided	Pathogenic (2)	criteria provided, single submitter	Jun 20, 2022	RCV000056481.4
Ichthyosis, annular epidermolytic 1	Pathogenic (1)	no assertion criteria provided	Feb 7, 2024	RCV004595904.1

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 (Jun 20, 2022)	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: SCV003441913.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 9856845 Comment: For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more) For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 66163). This missense change has been observed in individuals with autosomal dominant KRT10-related conditions (PMID: 9856845). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 446 of the KRT10 protein (p.Ile446Thr). (less)
Pathogenic (Feb 07, 2024)	no assertion criteria provided Method: literature only	ICHTHYOSIS, ANNULAR EPIDERMOLYTIC, 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV005088076.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (1) PubMed: 9856845 Comment on evidence: In a mother (III-3), daughter (IV-1), and son (IV-2) who had annular epidermolytic ichthyosis (AEI1; 607602), Suga et al. (1998) identified heterozygosity for a T-to-C … (more) In a mother (III-3), daughter (IV-1), and son (IV-2) who had annular epidermolytic ichthyosis (AEI1; 607602), Suga et al. (1998) identified heterozygosity for a T-to-C transition in the KRT10 gene, resulting in an ile107-to-thr (I107T) substitution at a highly conserved residue within the helix termination motif in the 2B segment of the rod domain. The mutation was not found in unaffected family members or in 50 unrelated controls, and the authors noted that no silent polymorphisms had been reported at that site. (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: SCV000087591.1 First in ClinVar: Oct 20, 2013 Last updated: Oct 20, 2013

Comment:

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 66163). This missense change has been observed in individuals with autosomal dominant KRT10-related conditions (PMID: 9856845). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 446 of the KRT10 protein (p.Ile446Thr).

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
A novel helix termination mutation in keratin 10 in annular epidermolytic ichthyosis, a variant of bullous congenital ichthyosiform erythroderma.	Suga Y	The Journal of investigative dermatology	1998	PMID: 9856845

Text-mined citations for rs62651994 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000421.5(KRT10):c.1337T>C (p.Ile446Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs62651994 ...