ClinVar Genomic variation as it relates to human health
NM_000128.4(F11):c.1247G>A (p.Cys416Tyr)
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_000128.4(F11):c.1247G>A (p.Cys416Tyr)
Variation ID: 371565 Accession: VCV000371565.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q35.2 4: 186284203 (GRCh38) [ NCBI UCSC ] 4: 187205357 (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 Jan 7, 2017 Feb 14, 2024 May 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000128.4:c.1247G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000119.1:p.Cys416Tyr missense NC_000004.12:g.186284203G>A NC_000004.11:g.187205357G>A NG_008051.1:g.23240G>A LRG_583:g.23240G>A LRG_583t1:c.1247G>A LRG_583p1:p.Cys416Tyr - Protein change
- C416Y
- Other names
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- Canonical SPDI
- NC_000004.12:186284202: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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
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
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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
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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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F11 | - | - |
GRCh38 GRCh37 |
494 | 810 |
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
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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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 17, 2020 | RCV000411689.10 | |
Pathogenic (1) |
criteria provided, single submitter
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May 30, 2023 | RCV002523881.3 |
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
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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
(Oct 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary factor XI deficiency disease
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915086.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The F11 c.1247G>A (p.Cys416Tyr) missense variant, also known as p.Cys398Tyr, has been reported in at least five studies in which it is found in at … (more)
The F11 c.1247G>A (p.Cys416Tyr) missense variant, also known as p.Cys398Tyr, has been reported in at least five studies in which it is found in at least 12 probands with factor XI deficiency, including in at least three in a homozygous state, in two in a compound heterozygous state, and in at least seven in a heterozygous state (Kravtsov et al. 2005; Mitchell et al. 2006; Zucker et al. 2007; Saunders et al. 2009; Kılıç et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.000089 in the Latino population of the Genome Aggregation Database. Functional studies in 293 and BHK fibroblasts demonstrated that the p.Cys416Tyr variant protein formed intracellular dimers but is poorly secreted, and demonstrates a dominant-negative effect on wildtype fXI secretion when cotransfected with wild type fXI (Kravtsov et al. 2005). Structural analysis indicated that the variant breaks the disulfide bridge between residues Cys398 and Cys414 disrupting folding of the serine protease domain of the protein (O'Connell et al. 2005; Saunders et al. 2009). Based on the evidence, the p.Cys416Tyr variant is classified as pathogenic for factor XI deficiency and has been described in cases following both autosomal dominant and recessive inheritance. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely pathogenic
(Oct 20, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hereditary factor XI deficiency disease
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000487179.2
First in ClinVar: Jan 07, 2017 Last updated: Dec 24, 2022 |
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Likely pathogenic
(Jan 17, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary factor XI deficiency disease
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024544.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(May 30, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003525895.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects F11 function (PMID: 15728123). Advanced modeling … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects F11 function (PMID: 15728123). 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) performed at Invitae indicates that this missense variant is expected to disrupt F11 protein function. ClinVar contains an entry for this variant (Variation ID: 371565). This variant is also known as p.Cys398Tyr. This missense change has been observed in individual(s) with autosomal recessive FXI deficiency (PMID: 16835901, 18024374, 25074526, 28960694). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant FXI deficiency (PMID: 15728123, 19652879, 28960694); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (rs779802284, gnomAD 0.009%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 416 of the F11 protein (p.Cys416Tyr). (less)
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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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High incidence of FXI deficiency in a Spanish town caused by 11 different mutations and the first duplication of F11: Results from the Yecla study. | Esteban J | Haemophilia : the official journal of the World Federation of Hemophilia | 2017 | PMID: 28960694 |
Spontaneous thrombosis in a patient with factor XI deficiency homozygous for the p.Cys398Tyr mutation. | Kılıç SÇ | Blood transfusion = Trasfusione del sangue | 2014 | PMID: 25074526 |
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 |
Characterization of seven novel mutations causing factor XI deficiency. | Zucker M | Haematologica | 2007 | PMID: 18024374 |
Spectrum of factor XI (F11) mutations in the UK population--116 index cases and 140 mutations. | Mitchell M | Human mutation | 2006 | PMID: 16835901 |
A classification system for cross-reactive material-negative factor XI deficiency. | Kravtsov DV | Blood | 2005 | PMID: 15728123 |
Structural interpretation of 42 mutations causing factor XI deficiency using homology modeling. | O'Connell NM | Journal of thrombosis and haemostasis : JTH | 2005 | PMID: 15634276 |
Text-mined citations for rs779802284 ...
HelpRecord 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.