The missense c.1432G>A (p.Gly478Arg) variant in the F11 gene has been observed in individuals with factor XI (FXI) deficiency (Mitchell, Michael et al.,2006). It has also been observed to segregate with disease in related individuals. This variant is reported with the allele frequency (0.01%) in the gnomAD Exomes and novel in 1000. It is submitted to ClinVar as Pathogenic/Likely Pathogenic. The amino acid Glycine at position 478 is changed to a Arginine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly478Arg in F11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000128.4(F11):c.1432G>A (p.Gly478Arg)
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.
(11)
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
11
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.1432G>A (p.Gly478Arg)
Variation ID: 285379 Accession: VCV000285379.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 4q35.2 4: 186285765 (GRCh38) [ NCBI UCSC ] 4: 187206919 (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 Apr 20, 2024 Apr 4, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000128.4:c.1432G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000119.1:p.Gly478Arg missense NC_000004.12:g.186285765G>A NC_000004.11:g.187206919G>A NG_008051.1:g.24802G>A LRG_583:g.24802G>A LRG_583t1:c.1432G>A LRG_583p1:p.Gly478Arg - Protein change
- G478R
- Other names
- -
- Canonical SPDI
- NC_000004.12:186285764:G:A
-
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.
-
0.00080 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00010
Exome Aggregation Consortium (ExAC) 0.00012
1000 Genomes Project 30x 0.00062
1000 Genomes Project 0.00080
- 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 | |
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/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Apr 4, 2024 | RCV000352684.17 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 25, 2024 | RCV000725651.11 | |
|
Plasma factor XI deficiency
|
Pathogenic (1) |
no assertion criteria provided
|
Feb 14, 2020 | RCV001828215.1 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jan 02, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary factor XI deficiency disease
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000678083.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
|
|
|
Pathogenic
(Dec 22, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000338374.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
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: SCV000899308.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Observation 1: Observation 2: |
|
|
Likely pathogenic
(Aug 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary factor XI deficiency disease
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002809762.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Likely pathogenic
(Feb 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary factor XI deficiency disease
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004176542.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The missense c.1432G>A (p.Gly478Arg) variant in the F11 gene has been observed in individuals with factor XI (FXI) deficiency (Mitchell, Michael et al.,2006). It has … (more)
The missense c.1432G>A (p.Gly478Arg) variant in the F11 gene has been observed in individuals with factor XI (FXI) deficiency (Mitchell, Michael et al.,2006). It has also been observed to segregate with disease in related individuals. This variant is reported with the allele frequency (0.01%) in the gnomAD Exomes and novel in 1000. It is submitted to ClinVar as Pathogenic/Likely Pathogenic. The amino acid Glycine at position 478 is changed to a Arginine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly478Arg in F11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Abnormality of blood and blood-forming tissues (present)
|
|
|
Likely pathogenic
(Aug 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary factor XI deficiency disease
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024546.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000946391.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 478 of the F11 protein (p.Gly478Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 478 of the F11 protein (p.Gly478Arg). This variant is present in population databases (rs542967227, gnomAD 0.07%). This missense change has been observed in individuals with autosomal recessive factor XI (FXI) deficiency and/or factor XI (FXI) deficiency (PMID: 15842381, 16079124, 16835901, 19652879, 26558335). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly460Arg. ClinVar contains an entry for this variant (Variation ID: 285379). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on F11 protein function. 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
(Apr 04, 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: SCV004809519.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
|
|
|
Pathogenic
(Nov 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary factor XI deficiency disease
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848810.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Gly478Arg ( historically referred to as Gly460Arg) variant in F11 has been reported in at least 5 homozygous, 2 compound heterozygous, and 2 heterozygous … (more)
The p.Gly478Arg ( historically referred to as Gly460Arg) variant in F11 has been reported in at least 5 homozygous, 2 compound heterozygous, and 2 heterozygous individuals with Hereditary factor XI deficiency disease. Majority of these individuals were noted to have reduced FXI:C and/or FXI:Ag levels (Mitchell 2003 PubMed: 12716376; Saunders 2009 PubMed: 19652879; Downes 2019 PubMed: 31064749; Jayandharan 2005 PMID: 15842381; Mitchell 2006 PMID: 16835901; Pike 2016 PMID: 26558335). It was also observed in ClinVar (Variation ID 285379) and in 0.14% (7/4828) of South Asian gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Hereditary factor XI deficiency disease; although, some heterozygotes may present with features. ACMG/AMP Criteria applied: PM3_VeryStrong, PP3, PP4. (less)
|
|
|
Pathogenic
(Feb 14, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Plasma factor XI deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002082950.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: research
|
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: SCV002515641.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022
Comment:
Submitted to GoldVariant by Dr Karyn Mégy from NIHR Bioresource - Cambridge University, UK
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|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 478 of the F11 protein (p.Gly478Arg). This variant is present in population databases (rs542967227, gnomAD 0.07%). This missense change has been observed in individuals with autosomal recessive factor XI (FXI) deficiency and/or factor XI (FXI) deficiency (PMID: 15842381, 16079124, 16835901, 19652879, 26558335). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly460Arg. ClinVar contains an entry for this variant (Variation ID: 285379). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on F11 protein function. 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.
Comment:
The p.Gly478Arg ( historically referred to as Gly460Arg) variant in F11 has been reported in at least 5 homozygous, 2 compound heterozygous, and 2 heterozygous individuals with Hereditary factor XI deficiency disease. Majority of these individuals were noted to have reduced FXI:C and/or FXI:Ag levels (Mitchell 2003 PubMed: 12716376; Saunders 2009 PubMed: 19652879; Downes 2019 PubMed: 31064749; Jayandharan 2005 PMID: 15842381; Mitchell 2006 PMID: 16835901; Pike 2016 PMID: 26558335). It was also observed in ClinVar (Variation ID 285379) and in 0.14% (7/4828) of South Asian gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Hereditary factor XI deficiency disease; although, some heterozygotes may present with features. ACMG/AMP Criteria applied: PM3_VeryStrong, PP3, PP4.
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 missense c.1432G>A (p.Gly478Arg) variant in the F11 gene has been observed in individuals with factor XI (FXI) deficiency (Mitchell, Michael et al.,2006). It has also been observed to segregate with disease in related individuals. This variant is reported with the allele frequency (0.01%) in the gnomAD Exomes and novel in 1000. It is submitted to ClinVar as Pathogenic/Likely Pathogenic. The amino acid Glycine at position 478 is changed to a Arginine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly478Arg in F11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 478 of the F11 protein (p.Gly478Arg). This variant is present in population databases (rs542967227, gnomAD 0.07%). This missense change has been observed in individuals with autosomal recessive factor XI (FXI) deficiency and/or factor XI (FXI) deficiency (PMID: 15842381, 16079124, 16835901, 19652879, 26558335). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly460Arg. ClinVar contains an entry for this variant (Variation ID: 285379). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on F11 protein function. 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.
Comment:
The p.Gly478Arg ( historically referred to as Gly460Arg) variant in F11 has been reported in at least 5 homozygous, 2 compound heterozygous, and 2 heterozygous individuals with Hereditary factor XI deficiency disease. Majority of these individuals were noted to have reduced FXI:C and/or FXI:Ag levels (Mitchell 2003 PubMed: 12716376; Saunders 2009 PubMed: 19652879; Downes 2019 PubMed: 31064749; Jayandharan 2005 PMID: 15842381; Mitchell 2006 PMID: 16835901; Pike 2016 PMID: 26558335). It was also observed in ClinVar (Variation ID 285379) and in 0.14% (7/4828) of South Asian gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Hereditary factor XI deficiency disease; although, some heterozygotes may present with features. ACMG/AMP Criteria applied: PM3_VeryStrong, PP3, PP4.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Structural analysis of eight novel and 112 previously reported missense mutations in the interactive FXI mutation database reveals new insight on FXI deficiency. | Saunders RE | Thrombosis and haemostasis | 2009 | PMID: 19652879 |
| Spectrum of factor XI (F11) mutations in the UK population--116 index cases and 140 mutations. | Mitchell M | Human mutation | 2006 | PMID: 16835901 |
| Factor XI deficiency: identification of six novel missense mutations (P23L, P69T, C92G, E243D, W497C and E547K). | Quélin F | Haematologica | 2005 | PMID: 16079124 |
| Novel missense mutations in two patients with factor XI deficiency (Val271Leu and Tyr351Ser) and one patient with combined factor XI and factor IX deficiency (Phe349Val). | Jayandharan G | Journal of thrombosis and haemostasis : JTH | 2005 | PMID: 15842381 |
| Eighteen unrelated patients with factor XI deficiency, four novel mutations and a 100% detection rate by denaturing high-performance liquid chromatography. | Mitchell M | British journal of haematology | 2003 | PMID: 12716376 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=F11 | - | - | - | - |
Text-mined citations for rs542967227 ...
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 Sep 29, 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.