VCV000968653.5 - ClinVar

NM_194454.3(KRIT1):c.1107_1109delinsCA (p.Glu369fs)

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, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_194454.3(KRIT1):c.1107_1109delinsCA (p.Glu369fs)

Variation ID: 968653 Accession: VCV000968653.5

Type and length

Indel, 3 bp

Location

Cytogenetic: 7q21.2 7: 92226563-92226565 (GRCh38) [ NCBI UCSC ] 7: 91855877-91855879 (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	Jul 16, 2020	Feb 20, 2024	Apr 4, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_194454.3:c.1107_1109delinsCA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_919436.1:p.Glu369fs	frameshift
NM_001013406.2:c.963_965delinsCA	NP_001013424.1:p.Glu321fs	frameshift
NM_001350669.1:c.963_965delinsCA	NP_001337598.1:p.Glu321fs	frameshift
NM_001350670.1:c.963_965delinsCA	NP_001337599.1:p.Glu321fs	frameshift
NM_001350671.1:c.393_395delinsCA	NP_001337600.1:p.Glu131fs	frameshift
NM_001350672.1:c.1107_1109delinsCA	NP_001337601.1:p.Glu369fs	frameshift
NM_001350673.1:c.1107_1109delinsCA	NP_001337602.1:p.Glu369fs	frameshift
NM_001350674.1:c.1107_1109delinsCA	NP_001337603.1:p.Glu369fs	frameshift
NM_001350675.1:c.1107_1109delinsCA	NP_001337604.1:p.Glu369fs	frameshift
NM_001350676.1:c.1107_1109delinsCA	NP_001337605.1:p.Glu369fs	frameshift
NM_001350677.1:c.1107_1109delinsCA	NP_001337606.1:p.Glu369fs	frameshift
NM_001350678.1:c.1107_1109delinsCA	NP_001337607.1:p.Glu369fs	frameshift
NM_001350679.1:c.1107_1109delinsCA	NP_001337608.1:p.Glu369fs	frameshift
NM_001350680.1:c.1107_1109delinsCA	NP_001337609.1:p.Glu369fs	frameshift
NM_001350681.1:c.1107_1109delinsCA	NP_001337610.1:p.Glu369fs	frameshift
NM_001350682.1:c.1107_1109delinsCA	NP_001337611.1:p.Glu369fs	frameshift
NM_001350683.1:c.1107_1109delinsCA	NP_001337612.1:p.Glu369fs	frameshift
NM_001350684.1:c.1107_1109delinsCA	NP_001337613.1:p.Glu369fs	frameshift
NM_001350685.1:c.1107_1109delinsCA	NP_001337614.1:p.Glu369fs	frameshift
NM_001350686.1:c.1107_1109delinsCA	NP_001337615.1:p.Glu369fs	frameshift
NM_001350687.1:c.1107_1109delinsCA	NP_001337616.1:p.Glu369fs	frameshift
NM_001350688.1:c.1107_1109delinsCA	NP_001337617.1:p.Glu369fs	frameshift
NM_001350689.1:c.1107_1109delinsCA	NP_001337618.1:p.Glu369fs	frameshift
NM_001350690.1:c.1107_1109delinsCA	NP_001337619.1:p.Glu369fs	frameshift
NM_001350691.1:c.1107_1109delinsCA	NP_001337620.1:p.Glu369fs	frameshift
NM_001350692.1:c.1107_1109delinsCA	NP_001337621.1:p.Glu369fs	frameshift
NM_001350693.1:c.1107_1109delinsCA	NP_001337622.1:p.Glu369fs	frameshift
NM_001350694.1:c.1107_1109delinsCA	NP_001337623.1:p.Glu369fs	frameshift
NM_001350695.1:c.1107_1109delinsCA	NP_001337624.1:p.Glu369fs	frameshift
NM_001350696.1:c.1107_1109delinsCA	NP_001337625.1:p.Glu369fs	frameshift
NM_001350697.1:c.1107_1109delinsCA	NP_001337626.1:p.Glu369fs	frameshift
NM_004912.4:c.1107_1109delinsCA	NP_004903.2:p.Glu369fs	frameshift
NM_194455.1:c.1107_1109delinsCA	NP_919437.1:p.Glu369fs	frameshift
NM_194456.1:c.1107_1109delinsCA	NP_919438.1:p.Glu369fs	frameshift
NC_000007.14:g.92226563_92226565delinsTG
NC_000007.13:g.91855877_91855879delinsTG
NG_012964.1:g.24536_24538delinsCA
LRG_650:g.24536_24538delinsCA
LRG_650t1:c.1107_1109delinsCA	LRG_650p1:p.Glu369fs

... more HGVS ... less HGVS

Protein change

E321fs, E369fs, E131fs

Other names

p.Glu369Aspfs*7

Canonical SPDI

NC_000007.14:92226562:ATT:TG

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

dbSNP: rs1796247872 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.
KRIT1		-	-	GRCh38 GRCh37	658	688

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.
Cerebral cavernous malformation	Pathogenic (1)	criteria provided, single submitter	Jan 20, 2023	RCV001243839.4
not provided	Pathogenic (1)	criteria provided, single submitter	Apr 4, 2023	RCV003481023.1

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 (Jan 20, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cerebral cavernous malformation Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001417022.3 First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024	Publications: PubMed (4) PubMed: 10508515‚ 11222804‚ 12404106‚ 24689081 Comment: This sequence change creates a premature translational stop signal (p.Glu369Aspfs7) in the KRIT1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Glu369Aspfs7) in the KRIT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KRIT1 are known to be pathogenic (PMID: 10508515, 11222804, 12404106, 24689081). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with KRIT1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). (less)
Pathogenic (Apr 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004226791.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Comment: PP4, PM2_supporting, PVS1 Number of individuals with the variant: 1

Comment:

This sequence change creates a premature translational stop signal (p.Glu369Aspfs*7) in the KRIT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KRIT1 are known to be pathogenic (PMID: 10508515, 11222804, 12404106, 24689081). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with KRIT1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%).

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
High mutation detection rates in cerebral cavernous malformation upon stringent inclusion criteria: one-third of probands are minors.	Spiegler S	Molecular genetics & genomic medicine	2014	PMID: 24689081
Spectrum and expression analysis of KRIT1 mutations in 121 consecutive and unrelated patients with Cerebral Cavernous Malformations.	Cavé-Riant F	European journal of human genetics : EJHG	2002	PMID: 12404106
CCM1 gene mutations in families segregating cerebral cavernous malformations.	Davenport WJ	Neurology	2001	PMID: 11222804
Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas.	Laberge-le Couteulx S	Nature genetics	1999	PMID: 10508515

Text-mined citations for rs1796247872 ...

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_194454.3(KRIT1):c.1107_1109delinsCA (p.Glu369fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1796247872 ...