Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23595507, 27649701, 22699465, 18300272, 20884211, 18383594, 33651268)
ClinVar Genomic variation as it relates to human health
NM_194454.3(KRIT1):c.1201_1204del (p.Gln401fs)
Germline
Classification
Help
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.
(7)
Help
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
7
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.1201_1204del (p.Gln401fs)
Variation ID: 372398 Accession: VCV000372398.20
- Type and length
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Microsatellite, 4 bp
- Location
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Cytogenetic: 7q21.2 7: 92225770-92225773 (GRCh38) [ NCBI UCSC ] 7: 91855084-91855087 (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 Jan 9, 2017 Nov 24, 2024 Jun 5, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_194454.3:c.1201_1204del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_919436.1:p.Gln401fs frameshift NM_194454.3:c.1201_1204delCAAA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001013406.2:c.1057_1060del NP_001013424.1:p.Gln353fs frameshift NM_001350669.1:c.1057_1060del NP_001337598.1:p.Gln353fs frameshift NM_001350670.1:c.1057_1060del NP_001337599.1:p.Gln353fs frameshift NM_001350671.1:c.487_490del NP_001337600.1:p.Gln163fs frameshift NM_001350672.1:c.1201_1204del NP_001337601.1:p.Gln401fs frameshift NM_001350673.1:c.1201_1204del NP_001337602.1:p.Gln401fs frameshift NM_001350674.1:c.1201_1204del NP_001337603.1:p.Gln401fs frameshift NM_001350675.1:c.1201_1204del NP_001337604.1:p.Gln401fs frameshift NM_001350676.1:c.1201_1204del NP_001337605.1:p.Gln401fs frameshift NM_001350677.1:c.1201_1204del NP_001337606.1:p.Gln401fs frameshift NM_001350678.1:c.1201_1204del NP_001337607.1:p.Gln401fs frameshift NM_001350679.1:c.1201_1204del NP_001337608.1:p.Gln401fs frameshift NM_001350680.1:c.1201_1204del NP_001337609.1:p.Gln401fs frameshift NM_001350681.1:c.1201_1204del NP_001337610.1:p.Gln401fs frameshift NM_001350682.1:c.1201_1204del NP_001337611.1:p.Gln401fs frameshift NM_001350683.1:c.1201_1204del NP_001337612.1:p.Gln401fs frameshift NM_001350684.1:c.1201_1204del NP_001337613.1:p.Gln401fs frameshift NM_001350685.1:c.1201_1204del NP_001337614.1:p.Gln401fs frameshift NM_001350686.1:c.1201_1204del NP_001337615.1:p.Gln401fs frameshift NM_001350687.1:c.1201_1204del NP_001337616.1:p.Gln401fs frameshift NM_001350688.1:c.1201_1204del NP_001337617.1:p.Gln401fs frameshift NM_001350689.1:c.1201_1204del NP_001337618.1:p.Gln401fs frameshift NM_001350690.1:c.1201_1204del NP_001337619.1:p.Gln401fs frameshift NM_001350691.1:c.1201_1204del NP_001337620.1:p.Gln401fs frameshift NM_001350692.1:c.1201_1204del NP_001337621.1:p.Gln401fs frameshift NM_001350693.1:c.1201_1204del NP_001337622.1:p.Gln401fs frameshift NM_001350694.1:c.1201_1204del NP_001337623.1:p.Gln401fs frameshift NM_001350695.1:c.1201_1204del NP_001337624.1:p.Gln401fs frameshift NM_001350696.1:c.1201_1204del NP_001337625.1:p.Gln401fs frameshift NM_001350697.1:c.1201_1204del NP_001337626.1:p.Gln401fs frameshift NM_004912.4:c.1201_1204del NP_004903.2:p.Gln401fs frameshift NM_194455.1:c.1201_1204del NP_919437.1:p.Gln401fs frameshift NM_194456.1:c.1201_1204del NP_919438.1:p.Gln401fs frameshift NM_194456.1:c.1201_1204delCAAA NC_000007.14:g.92225773GTTT[1] NC_000007.13:g.91855087GTTT[1] NG_012964.1:g.25324CAAA[1] LRG_650:g.25324CAAA[1] LRG_650t1:c.1201_1204del LRG_650p1:p.Gln401fs - Protein change
- Q353fs, Q401fs, Q163fs
- Other names
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p.Gln401Thrfs*10
- Canonical SPDI
- NC_000007.14:92225769:TTTGTTTGTTT:TTTGTTT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jun 5, 2024 | RCV000414484.9 | |
| Pathogenic (3) |
criteria provided, single submitter
|
Jul 12, 2023 | RCV000816950.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 20, 2022 | RCV003447526.1 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Jun 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000852966.1
First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017 |
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Pathogenic
(Jul 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000490587.5
First in ClinVar: Jan 09, 2017 Last updated: Aug 13, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23595507, 27649701, 22699465, 18300272, 20884211, 18383594, 33651268) (less)
|
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Pathogenic
(Jul 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cerebral cavernous malformation
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000957480.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln401Thrfs*10) 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.Gln401Thrfs*10) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with cerebral cavernous malformations (PMID: 2359550, 18300272, 20884211, 22699465, 27649701; Invitae). This variant is also known as c.1197_1200delCAAA. ClinVar contains an entry for this variant (Variation ID: 372398). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cavernous hemangioma of brain
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175585.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
|
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Pathogenic
(Jun 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005413788.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PP1_strong, PP4, PM2, PS4_moderate, PVS1
Number of individuals with the variant: 1
|
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Pathogenic
(Oct 06, 2021)
|
no assertion criteria provided
Method: research
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Cerebral cavernous malformation
Affected status: yes
Allele origin:
unknown
|
Laboratory of Medical Genetics, University of Torino
Accession: SCV001976510.1
First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Uncertain significance
(Jan 01, 2016)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Cerebral cavernous malformation
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366349.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP4,PP5.
|
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| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Gln401Thrfs*10) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with cerebral cavernous malformations (PMID: 2359550, 18300272, 20884211, 22699465, 27649701; Invitae). This variant is also known as c.1197_1200delCAAA. ClinVar contains an entry for this variant (Variation ID: 372398). For these reasons, this variant has been classified as Pathogenic.
Comment:
PP1_strong, PP4, PM2, PS4_moderate, PVS1
Comment:
This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP4,PP5.
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:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23595507, 27649701, 22699465, 18300272, 20884211, 18383594, 33651268)
Comment:
This sequence change creates a premature translational stop signal (p.Gln401Thrfs*10) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with cerebral cavernous malformations (PMID: 2359550, 18300272, 20884211, 22699465, 27649701; Invitae). This variant is also known as c.1197_1200delCAAA. ClinVar contains an entry for this variant (Variation ID: 372398). For these reasons, this variant has been classified as Pathogenic.
Comment:
PP1_strong, PP4, PM2, PS4_moderate, PVS1
Comment:
This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP4,PP5.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A tangled web: Dual diagnosis of hereditary hemorrhagic telangiectasia and familial cerebral cavernous malformation. | Kumar M | Pediatric blood & cancer | 2023 | PMID: 37336838 |
| KRIT1 Gene in Patients with Cerebral Cavernous Malformations: Clinical Features and Molecular Characterization of Novel Variants. | Ricci C | Journal of molecular neuroscience : MN | 2021 | PMID: 33651268 |
| Identification of a Novel Deletion Mutation (c.1780delG) and a Novel Splice-Site Mutation (c.1412-1G>A) in the CCM1/KRIT1 Gene Associated with Familial Cerebral Cavernous Malformation in the Chinese Population. | Yang C | Journal of molecular neuroscience : MN | 2017 | PMID: 27649701 |
| 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 |
| Familial cerebral cavernomas due to a KRIT1 mutation presenting with epilepsy. | Rajakulendran S | BMJ case reports | 2011 | PMID: 22699465 |
| A novel CCM1 gene mutation causes cerebral cavernous malformation in a Chinese family. | Zhao Y | Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia | 2011 | PMID: 20884211 |
| Novel CCM1, CCM2, and CCM3 mutations in patients with cerebral cavernous malformations: in-frame deletion in CCM2 prevents formation of a CCM1/CCM2/CCM3 protein complex. | Stahl S | Human mutation | 2008 | PMID: 18300272 |
| Novel human pathological mutations. Gene symbol: KRIT1. Disease: cerebral cavernous malformation. | Limaye N | Human genetics | 2007 | PMID: 18383591 |
| 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 |
| Contraceptive use for planned parenthood patients. | Savel LE | New Jersey medicine : the journal of the Medical Society of New Jersey | 1990 | PMID: 2359550 |
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Text-mined citations for rs1057517753 ...
HelpThese 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 Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.