ClinVar Genomic variation as it relates to human health
NM_194454.3(KRIT1):c.1363C>T (p.Gln455Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_194454.3(KRIT1):c.1363C>T (p.Gln455Ter)
Variation ID: 5721 Accession: VCV000005721.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q21.2 7: 92222870 (GRCh38) [ NCBI UCSC ] 7: 91852184 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Aug 22, 2016 Mar 16, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_194454.3:c.1363C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_919436.1:p.Gln455Ter nonsense NM_001013406.2:c.1219C>T NP_001013424.1:p.Gln407Ter nonsense NM_001350669.1:c.1219C>T NP_001337598.1:p.Gln407Ter nonsense NM_001350670.1:c.1219C>T NP_001337599.1:p.Gln407Ter nonsense NM_001350671.1:c.649C>T NP_001337600.1:p.Gln217Ter nonsense NM_001350672.1:c.1363C>T NP_001337601.1:p.Gln455Ter nonsense NM_001350673.1:c.1363C>T NP_001337602.1:p.Gln455Ter nonsense NM_001350674.1:c.1363C>T NP_001337603.1:p.Gln455Ter nonsense NM_001350675.1:c.1363C>T NP_001337604.1:p.Gln455Ter nonsense NM_001350676.1:c.1363C>T NP_001337605.1:p.Gln455Ter nonsense NM_001350677.1:c.1363C>T NP_001337606.1:p.Gln455Ter nonsense NM_001350678.1:c.1363C>T NP_001337607.1:p.Gln455Ter nonsense NM_001350679.1:c.1363C>T NP_001337608.1:p.Gln455Ter nonsense NM_001350680.1:c.1363C>T NP_001337609.1:p.Gln455Ter nonsense NM_001350681.1:c.1363C>T NP_001337610.1:p.Gln455Ter nonsense NM_001350682.1:c.1363C>T NP_001337611.1:p.Gln455Ter nonsense NM_001350683.1:c.1363C>T NP_001337612.1:p.Gln455Ter nonsense NM_001350684.1:c.1363C>T NP_001337613.1:p.Gln455Ter nonsense NM_001350685.1:c.1363C>T NP_001337614.1:p.Gln455Ter nonsense NM_001350686.1:c.1363C>T NP_001337615.1:p.Gln455Ter nonsense NM_001350687.1:c.1363C>T NP_001337616.1:p.Gln455Ter nonsense NM_001350688.1:c.1363C>T NP_001337617.1:p.Gln455Ter nonsense NM_001350689.1:c.1363C>T NP_001337618.1:p.Gln455Ter nonsense NM_001350690.1:c.1363C>T NP_001337619.1:p.Gln455Ter nonsense NM_001350691.1:c.1363C>T NP_001337620.1:p.Gln455Ter nonsense NM_001350692.1:c.1363C>T NP_001337621.1:p.Gln455Ter nonsense NM_001350693.1:c.1363C>T NP_001337622.1:p.Gln455Ter nonsense NM_001350694.1:c.1363C>T NP_001337623.1:p.Gln455Ter nonsense NM_001350695.1:c.1363C>T NP_001337624.1:p.Gln455Ter nonsense NM_001350696.1:c.1363C>T NP_001337625.1:p.Gln455Ter nonsense NM_001350697.1:c.1363C>T NP_001337626.1:p.Gln455Ter nonsense NM_004912.4:c.1363C>T NP_004903.2:p.Gln455Ter nonsense NM_194455.1:c.1363C>T NP_919437.1:p.Gln455Ter nonsense NM_194456.1:c.1363C>T NP_919438.1:p.Gln455Ter nonsense NC_000007.14:g.92222870G>A NC_000007.13:g.91852184G>A NG_012964.1:g.28231C>T LRG_650:g.28231C>T LRG_650t1:c.1363C>T LRG_650p1:p.Gln455Ter - Protein change
- Q407*, Q455*, Q217*
- Other names
- Q248*
- Canonical SPDI
- NC_000007.14:92222869:G:A
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 | ||
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HI score
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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. |
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KRIT1 | - | - |
GRCh38 GRCh37 |
620 | 649 |
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. |
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Pathogenic (1) |
no assertion criteria provided
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Nov 1, 1999 | RCV000006075.12 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 21, 2023 | RCV000256079.24 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000239441.30 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 23, 2017 | RCV000506458.16 | |
KRIT1-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Dec 1, 2023 | RCV004547460.1 |
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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Pathogenic
(Jun 19, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000332319.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Jul 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cerebral cavernous malformation
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV002034855.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
Comment:
The KRIT1 c.1363C>T (p.Gln455Ter) variant, also described as c.742C>T (p.Gln248Ter), is a stop-gained variant that has been reported in the literature as a Hispanic-American founder … (more)
The KRIT1 c.1363C>T (p.Gln455Ter) variant, also described as c.742C>T (p.Gln248Ter), is a stop-gained variant that has been reported in the literature as a Hispanic-American founder variant in individuals and families with cerebral cavernous malformation (CCM) and has been identified in the majority of affected families with ancestry from northern Mexico and the American Southwest (Sahoo et al. 1999; Laurans et al. 2003; Morrison & Akers 2003; Choquet et al. 2014). The p.Gln455Ter was also identified in sporadic cases with no known family history of CCM, and in affected individuals of other ethnicities (Cave-Riant et al. 2002; Laurans et al. 2003; Denier et al. 2004). The p.Gln455Ter variant is reported at a frequency of 0.000029 in the Latino/Admixed American population of the Genome Aggregation Database (version 2.1.1), but this is based on one allele in a region of good sequencing coverage so the variant is presumed to be rare. Based on the available evidence, the p.Gln455Ter variant is classified as pathogenic for cerebral cavernous malformation. (less)
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Pathogenic
(Dec 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cerebral cavernous malformation
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003818910.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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KRIT1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000852980.3
First in ClinVar: Mar 08, 2017 Last updated: Mar 16, 2024 |
Comment:
The KRIT1 c.1363C>T variant is predicted to result in premature protein termination (p.Gln455*). This variant is known as the “Common Hispanic Mutation” and has been … (more)
The KRIT1 c.1363C>T variant is predicted to result in premature protein termination (p.Gln455*). This variant is known as the “Common Hispanic Mutation” and has been conclusively shown to be causative for cerebral cavernous malformations (CCMs) (Laurans et al. 2003. PubMed ID: 12854741; Choquet et al. 2014. PubMed ID: 24401931). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Feb 23, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604085.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Pathogenic
(Apr 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cerebral cavernous malformation
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894440.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Nov 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000321813.9
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Nonsense 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)
Nonsense 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 a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20096038, 29593473, 12854741, 19088123, 8596595, 25525159, 25896717, 10545614, 28489816, 29088464, 25556204, 24698976, 24401931, 12404106, 31254430, 9065560, 32100472) (less)
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Pathogenic
(Feb 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV001143454.4
First in ClinVar: Jan 19, 2020 Last updated: Jan 26, 2024 |
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with … (more)
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This is a common variant associated with cerebral cavernous malformations (CCM) in individuals of Hispanic-American descent (PMID: 10545614, 12854741, 24401931). In some published literature, this variant is referred to as c.742C>T (p.Gln248*). (less)
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cerebral cavernous malformation
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000644708.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln455*) 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.Gln455*) 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 present in population databases (rs267607203, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with cerebral cavernous malformations (PMID: 10545614, 12404106, 24401931). It is commonly reported in individuals of Hispanic-American ancestry (PMID: 10545614, 24401931). This variant is also known as c.742C>T (p.Gln248*). ClinVar contains an entry for this variant (Variation ID: 5721). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 01, 1999)
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no assertion criteria provided
Method: literature only
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CEREBRAL CAVERNOUS MALFORMATIONS 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026257.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 24, 2019 |
Comment on evidence:
In 16 of 21 Mexican American families with cerebral cavernous malformations (CCM1; 116860) analyzed, Sahoo et al. (1999) found that the KRIT1 gene harbored a … (more)
In 16 of 21 Mexican American families with cerebral cavernous malformations (CCM1; 116860) analyzed, Sahoo et al. (1999) found that the KRIT1 gene harbored a 1-bp transition (742C-T), changing a gln to a premature termination codon (Q248X). Distinct mutations in KRIT1 were identified in other Mexican American families, as well as in non-Hispanic Caucasian families. The apparently high frequency of cerebral cavernous malformations in Mexican Americans had been noted by Rigamonti et al. (1988) and Kattapong et al. (1995). The finding of a common disease haplotype in affected kindreds from this population had suggested a founder effect. Due to numbering differences, this mutation is also known as gln455 to ter (Q455X, rs267607203). (less)
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not provided
(-)
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no classification provided
Method: literature only
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Cerebral cavernous malformation
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000297819.2
First in ClinVar: Aug 22, 2016 Last updated: Oct 01, 2022 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Familial Cerebral Cavernous Malformations. | Adam MP | - | 2023 | PMID: 20301470 |
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 |
Association of cardiovascular risk factors with disease severity in cerebral cavernous malformation type 1 subjects with the common Hispanic mutation. | Choquet H | Cerebrovascular diseases (Basel, Switzerland) | 2014 | PMID: 24401931 |
Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis. | Akers AL | Human molecular genetics | 2009 | PMID: 19088123 |
Clinical features of cerebral cavernous malformations patients with KRIT1 mutations. | Denier C | Annals of neurology | 2004 | PMID: 14755725 |
Mutational analysis of 206 families with cavernous malformations. | Laurans MS | Journal of neurosurgery | 2003 | PMID: 12854741 |
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 |
Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). | Sahoo T | Human molecular genetics | 1999 | PMID: 10545614 |
Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. | Laberge-le Couteulx S | Nature genetics | 1999 | PMID: 10508515 |
Linkage of the locus for cerebral cavernous hemangiomas to human chromosome 7q in four families of Mexican-American descent. | Polymeropoulos MH | Neurology | 1997 | PMID: 9065560 |
Familial cerebral cavernous angiomas: clinical and radiologic studies. | Kattapong VJ | Neurology | 1995 | PMID: 7898703 |
Cerebral cavernous malformations. Incidence and familial occurrence. | Rigamonti D | The New England journal of medicine | 1988 | PMID: 3393196 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=KRIT1 | - | - | - | - |
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Text-mined citations for rs267607203 ...
HelpRecord last updated May 27, 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.