VCV000014582.3 - ClinVar

NM_000421.5(KRT10):c.1373+1G>A

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.

(2)

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.1373+1G>A

Variation ID: 14582 Accession: VCV000014582.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.2 17: 40819516 (GRCh38) [ NCBI UCSC ] 17: 38975768 (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	Mar 14, 2014	Mar 18, 2023	Feb 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000421.5:c.1373+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001379366.1:c.1373+1G>A		splice donor
NC_000017.11:g.40819516C>T
NC_000017.10:g.38975768C>T
NG_008405.1:g.8096G>A
NG_008405.2:g.8098G>A

... more HGVS ... less HGVS

Protein change

Other names

IVS6DS, G-A, +1

Canonical SPDI

NC_000017.11:40819515:C:T

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: CA124149 OMIM: 148080.0016 dbSNP: rs587776816 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 20798280 Table S2 to determine the location of this variant on the current reference sequence.

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	210
KRT10-AS1	-	-	-	GRCh38 GRCh37	21	136

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.
Congenital reticular ichthyosiform erythroderma	Pathogenic (2)	criteria provided, single submitter	Feb 23, 2023	RCV000015683.29

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 (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital reticular ichthyosiform erythroderma Affected status: yes Allele origin: unknown	3billion Accession: SCV003841767.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 20798280 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to alter splicing and result in a loss or disruption of … (more) The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported to be associated with KRT10 related disorder (PMID: 20798280). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Congenital ichthyosiform erythroderma (present) , Erythroderma (present) , Dry skin (present) , Scaling skin (present) , Congenital ichthyosiform erythroderma (present)
Pathogenic (Oct 01, 2010)	no assertion criteria provided Method: literature only	ICHTHYOSIS WITH CONFETTI Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035948.4 First in ClinVar: Apr 04, 2013 Last updated: Sep 10, 2021	Publications: PubMed (1) PubMed: 20798280 Comment on evidence: In a mother and 2 of her offspring, all affected with ichthyosis with confetti (IWC; 609165), Choate et al. (2010) identified a G-to-A transition at … (more) In a mother and 2 of her offspring, all affected with ichthyosis with confetti (IWC; 609165), Choate et al. (2010) identified a G-to-A transition at the +1 position of the intron 6 splice donor site of KRT10. The mutation resulted in skipping of exon 6 with a junction between exons 5 and 7 (delK386-S458, Gly459PhefsTer122). This mutation generated a protein with an arginine-rich C terminus that redirected keratin-10 from the cytokeratin filament network to the nucleolus. (less)

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported to be associated with KRT10 related disorder (PMID: 20798280). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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
Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10.	Choate KA	Science (New York, N.Y.)	2010	PMID: 20798280

Text-mined citations for rs587776816 ...

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 Aug 06, 2023

ClinVar Genomic variation as it relates to human health

NM_000421.5(KRT10):c.1373+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587776816 ...