The F11 c.1489C>T (p.R497*) nonsense variant is predicted to result in premature protein termination and/or nonsense-mediated decay. This variant has been reported previously as a single heterozygous variant in an individual with Factor XI deficiency (PMID: 16835901) and in the compound heterozygous state in an individual with Factor XI deficiency (PMID: 26558335).
ClinVar Genomic variation as it relates to human health
NM_000128.4(F11):c.1489C>T (p.Arg497Ter)
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.
(12)
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/Likely pathogenic
12
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000128.4(F11):c.1489C>T (p.Arg497Ter)
Variation ID: 280137 Accession: VCV000280137.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 4q35.2 4: 186286423 (GRCh38) [ NCBI UCSC ] 4: 187207577 (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 Dec 6, 2016 Sep 29, 2024 Mar 29, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000128.4:c.1489C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000119.1:p.Arg497Ter nonsense NC_000004.12:g.186286423C>T NC_000004.11:g.187207577C>T NG_008051.1:g.25460C>T LRG_583:g.25460C>T LRG_583t1:c.1489C>T LRG_583p1:p.Arg497Ter - Protein change
- R497*
- Other names
- -
- Canonical SPDI
- NC_000004.12:186286422:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- 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. |
|||
| F11 | - | - |
GRCh38 GRCh37 |
495 | 811 | |
| F11-AS1 | - | - | - | GRCh38 | - | 233 |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 29, 2023 | RCV000349831.7 | |
| Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Mar 29, 2024 | RCV000763125.15 | |
|
F11-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Dec 22, 2022 | RCV003409399.4 |
|
Plasma factor XI deficiency
|
Pathogenic (1) |
no assertion criteria provided
|
Sep 16, 2020 | RCV001273725.1 |
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
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary factor XI deficiency disease
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893676.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Likely pathogenic
(Feb 01, 2019)
|
criteria provided, single submitter
Method: research
|
Hereditary factor XI deficiency disease
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Study: ThromboGenomics
Accession: SCV000899310.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Observation 1:
Sex: male
Ethnicity/Population group: European
Observation 2:
Sex: male
Ethnicity/Population group: European
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Hereditary factor XI deficiency disease
Affected status: no
Allele origin:
germline
|
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251505.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
The F11 c.1489C>T (p.R497*) nonsense variant is predicted to result in premature protein termination and/or nonsense-mediated decay. This variant has been reported previously as a … (more)
The F11 c.1489C>T (p.R497*) nonsense variant is predicted to result in premature protein termination and/or nonsense-mediated decay. This variant has been reported previously as a single heterozygous variant in an individual with Factor XI deficiency (PMID: 16835901) and in the compound heterozygous state in an individual with Factor XI deficiency (PMID: 26558335). (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Nov 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000330014.9
First in ClinVar: Dec 06, 2016 Last updated: Sep 29, 2024 |
Comment:
Identified in the heterozygous state or with a second F11 variant in individuals with features of factor XI deficiency in published literature (PMID: 16835901, 26558335, … (more)
Identified in the heterozygous state or with a second F11 variant in individuals with features of factor XI deficiency in published literature (PMID: 16835901, 26558335, 32853555); 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 31064749, 31589614, 16835901, 32853555, 26558335) (less)
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary factor XI deficiency disease
Affected status: yes
Allele origin:
unknown
|
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002500853.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
Comment:
GoldVariant submitter: Kathleen Freson Center for Molecular and Vascular Biology, Leuven, Belgium
|
Observation 1:
Clinical Features:
Low factor 11 (present)
Observation 2:
Clinical Features:
Low factor 11 (present)
|
|
|
Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary factor XI deficiency disease
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002519642.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
|
Pathogenic
(Nov 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary factor XI deficiency disease
Affected status: unknown
Allele origin:
germline
|
DASA
Accession: SCV002588790.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
The c.1489C>T;p.(Arg497*) variant creates a premature translational stop signal in the F11 gene. It is expected to result in an absent or disrupted protein product … (more)
The c.1489C>T;p.(Arg497*) variant creates a premature translational stop signal in the F11 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 280137; PMID: 31064749, PMID: 16835901) - PS4. The variant is present at low allele frequencies population databases (rs375422404 – gnomAD 0.0001193%; ABraOM 0.000427 frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
|
|
|
Pathogenic
(Dec 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
F11-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004114003.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The F11 c.1489C>T variant is predicted to result in premature protein termination (p.Arg497*). This variant has been reported in individuals with Factor XI deficiency (Mitchell … (more)
The F11 c.1489C>T variant is predicted to result in premature protein termination (p.Arg497*). This variant has been reported in individuals with Factor XI deficiency (Mitchell et al. 2006. PubMed ID: 16835901; Table S3, Downes et al. 2019. PubMed ID: 31064749). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-187207577-C-T). In ClinVar, this variant is interpreted as likely pathogenic/pathogenic (https://preview.ncbi.nlm.nih.gov/clinvar/variation/280137/). Nonsense variants in F11 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Jun 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary factor XI deficiency disease
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002022261.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Oct 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002230649.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg497*) in the F11 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg497*) in the F11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in F11 are known to be pathogenic (PMID: 23929304). This variant is present in population databases (rs375422404, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with factor XI deficiency (PMID: 16835901, 26558335). ClinVar contains an entry for this variant (Variation ID: 280137). 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)
|
|
|
Pathogenic
(Mar 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary factor XI deficiency disease
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805724.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Plasma factor XI deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001457107.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Identified in the heterozygous state or with a second F11 variant in individuals with features of factor XI deficiency in published literature (PMID: 16835901, 26558335, 32853555); 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 31064749, 31589614, 16835901, 32853555, 26558335)
Comment:
The c.1489C>T;p.(Arg497*) variant creates a premature translational stop signal in the F11 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 280137; PMID: 31064749, PMID: 16835901) - PS4. The variant is present at low allele frequencies population databases (rs375422404 – gnomAD 0.0001193%; ABraOM 0.000427 frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
The F11 c.1489C>T variant is predicted to result in premature protein termination (p.Arg497*). This variant has been reported in individuals with Factor XI deficiency (Mitchell et al. 2006. PubMed ID: 16835901; Table S3, Downes et al. 2019. PubMed ID: 31064749). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-187207577-C-T). In ClinVar, this variant is interpreted as likely pathogenic/pathogenic (https://preview.ncbi.nlm.nih.gov/clinvar/variation/280137/). Nonsense variants in F11 are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg497*) in the F11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in F11 are known to be pathogenic (PMID: 23929304). This variant is present in population databases (rs375422404, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with factor XI deficiency (PMID: 16835901, 26558335). ClinVar contains an entry for this variant (Variation ID: 280137). 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.
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:
The F11 c.1489C>T (p.R497*) nonsense variant is predicted to result in premature protein termination and/or nonsense-mediated decay. This variant has been reported previously as a single heterozygous variant in an individual with Factor XI deficiency (PMID: 16835901) and in the compound heterozygous state in an individual with Factor XI deficiency (PMID: 26558335).
Comment:
Identified in the heterozygous state or with a second F11 variant in individuals with features of factor XI deficiency in published literature (PMID: 16835901, 26558335, 32853555); 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 31064749, 31589614, 16835901, 32853555, 26558335)
Comment:
The c.1489C>T;p.(Arg497*) variant creates a premature translational stop signal in the F11 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 280137; PMID: 31064749, PMID: 16835901) - PS4. The variant is present at low allele frequencies population databases (rs375422404 – gnomAD 0.0001193%; ABraOM 0.000427 frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
The F11 c.1489C>T variant is predicted to result in premature protein termination (p.Arg497*). This variant has been reported in individuals with Factor XI deficiency (Mitchell et al. 2006. PubMed ID: 16835901; Table S3, Downes et al. 2019. PubMed ID: 31064749). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-187207577-C-T). In ClinVar, this variant is interpreted as likely pathogenic/pathogenic (https://preview.ncbi.nlm.nih.gov/clinvar/variation/280137/). Nonsense variants in F11 are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg497*) in the F11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in F11 are known to be pathogenic (PMID: 23929304). This variant is present in population databases (rs375422404, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with factor XI deficiency (PMID: 16835901, 26558335). ClinVar contains an entry for this variant (Variation ID: 280137). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| GoldVariants, a resource for sharing rare genetic variants detected in bleeding, thrombotic, and platelet disorders: Communication from the ISTH SSC Subcommittee on Genomics in Thrombosis and Hemostasis. | Megy K | Journal of thrombosis and haemostasis : JTH | 2021 | PMID: 34355501 |
| Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. | Downes K | Blood | 2019 | PMID: 31064749 |
| In vitro comparison of the effect of two factor XI (FXI) concentrates on thrombin generation in major FXI deficiency. | Pike GN | Haemophilia : the official journal of the World Federation of Hemophilia | 2016 | PMID: 26558335 |
| Congenital factor XI deficiency: an update. | Duga S | Seminars in thrombosis and hemostasis | 2013 | PMID: 23929304 |
| Spectrum of factor XI (F11) mutations in the UK population--116 index cases and 140 mutations. | Mitchell M | Human mutation | 2006 | PMID: 16835901 |
Text-mined citations for rs375422404 ...
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 Oct 08, 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.