ClinVar Genomic variation as it relates to human health
NM_000133.4(F9):c.571C>T (p.Arg191Cys)
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_000133.4(F9):c.571C>T (p.Arg191Cys)
Variation ID: 10584 Accession: VCV000010584.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq27.1 X: 139551112 (GRCh38) [ NCBI UCSC ] X: 138633271 (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 Oct 12, 2017 Sep 16, 2024 Feb 23, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000133.4:c.571C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000124.1:p.Arg191Cys missense NM_001313913.2:c.457C>T NP_001300842.1:p.Arg153Cys missense NC_000023.11:g.139551112C>T NC_000023.10:g.138633271C>T NG_007994.1:g.25377C>T LRG_556:g.25377C>T LRG_556t1:c.571C>T LRG_556p1:p.Arg191Cys P00740:p.Arg191Cys - Protein change
- R191C, R153C
- Other names
- F9, ARG145CYS
- R145C
- Canonical SPDI
- NC_000023.11:139551111:C:T
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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
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00005
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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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F9 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
581 | 765 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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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 (5) |
criteria provided, multiple submitters, no conflicts
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Jun 28, 2022 | RCV000011330.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 8, 2022 | RCV001390295.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 23, 2024 | RCV004700216.1 |
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
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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
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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
(Jun 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary factor IX deficiency disease
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002556203.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Variant summary: F9 c.571C>T (p.Arg191Cys) results in a non-conservative amino acid change located in the cleavage site of the activated peptide (Hamasaki-Katagiri_2012) of the encoded … (more)
Variant summary: F9 c.571C>T (p.Arg191Cys) results in a non-conservative amino acid change located in the cleavage site of the activated peptide (Hamasaki-Katagiri_2012) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 183448 control chromosomes. c.571C>T has been reported in the literature in multiple individuals affected with Factor IX Deficiency (Hemophilia B) (example, Knobloch_1993, Chavali_2009, Hamasaki-Katagiri_2012, Marliere_2020, Parrado Jara_2020). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(May 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary factor IX deficiency disease
(X-linked recessive inheritance)
Affected status: not applicable
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556900.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Feb 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Thrombophilia, X-linked, due to factor 9 defect
Hereditary factor IX deficiency disease
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001591978.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
This variant disrupts the p.Arg191 amino acid residue in F9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19699296). This … (more)
This variant disrupts the p.Arg191 amino acid residue in F9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19699296). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 10584). This missense change has been observed in individuals with F9-related conditions (PMID: 1615486, 19699296, 27109384). This variant is present in population databases (rs137852237, gnomAD 0.001%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 191 of the F9 protein (p.Arg191Cys). (less)
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Pathogenic
(Feb 23, 2024)
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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: SCV005201733.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Published functional studies demonstrate a damaging effect (PMID: 28440032); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this … (more)
Published functional studies demonstrate a damaging effect (PMID: 28440032); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19699296, 31840356, 32155688, 1615486, 22639855, 27109384, 28440032, 38196513) (less)
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Pathogenic
(Aug 01, 1989)
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no assertion criteria provided
Method: literature only
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HEMOPHILIA B
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000031561.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 12, 2017 |
Comment on evidence:
Liddell et al. (1989) described a molecular defect in factor IX Cardiff, a variant that showed faulty activation with the production of a stable reaction … (more)
Liddell et al. (1989) described a molecular defect in factor IX Cardiff, a variant that showed faulty activation with the production of a stable reaction product with a molecular weight compatible with that of a putative light chain-activation intermediate. A single C-to-T transition was discovered that changed the arg residue at position 145 (the first residue of the first bond in the activation peptide) to a cys. The hemophilia (306900) was clinically moderate to severe. (less)
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Pathogenic
(Jun 01, 2019)
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no assertion criteria provided
Method: clinical testing
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Hereditary factor IX deficiency disease
Affected status: yes
Allele origin:
germline
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Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
Accession: SCV001424896.1
First in ClinVar: Nov 19, 2020 Last updated: Nov 19, 2020 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Causasians
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Hereditary factor IX deficiency disease
Affected status: yes
Allele origin:
maternal
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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002515587.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022
Comment:
Submitted to GoldVariant by Bilal Jradeh from Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, UK
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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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Molecular characterization of hemophilia B patients in Colombia. | Parrado Jara YA | Molecular genetics & genomic medicine | 2020 | PMID: 32155688 |
EHL-FIX in haemophilia B carriers with FIX deficiency. | Marlière C | Haemophilia : the official journal of the World Federation of Hemophilia | 2020 | PMID: 31840356 |
A genetic analysis of 23 Chinese patients with hemophilia B. | Wang QY | Scientific reports | 2016 | PMID: 27109384 |
Assessment of the F9 genotype-specific FIX inhibitor risks and characterisation of 10 novel severe F9 defects in the first molecular series of Argentinian patients with haemophilia B. | Radic CP | Thrombosis and haemostasis | 2013 | PMID: 23093250 |
Analysis of F9 point mutations and their correlation to severity of haemophilia B disease. | Hamasaki-Katagiri N | Haemophilia : the official journal of the World Federation of Hemophilia | 2012 | PMID: 22639855 |
Hemophilia B is a quasi-quantitative condition with certain mutations showing phenotypic plasticity. | Chavali S | Genomics | 2009 | PMID: 19699296 |
Molecular characterization of factor IX gene mutations in 53 patients with haemophilia B in India. | Jayandharan GR | Thrombosis and haemostasis | 2005 | PMID: 16270648 |
Molecular genotyping of the Italian cohort of patients with hemophilia B. | Belvini D | Haematologica | 2005 | PMID: 15921378 |
Molecular pathology of haemophilia B: identification of five novel mutations including a LINE 1 insertion in Indian patients. | Mukherjee S | Haemophilia : the official journal of the World Federation of Hemophilia | 2004 | PMID: 15086324 |
Haemophilia B mutations in Sweden: a population-based study of mutational heterogeneity. | Ljung R | British journal of haematology | 2001 | PMID: 11328285 |
Factor IX gene sequencing by a simple and sensitive 15-hour procedure for haemophilia B diagnosis: identification of two novel mutations. | Vidal F | British journal of haematology | 2000 | PMID: 11122099 |
Factor IX mutations in South Africans and African Americans are compatible with primarily endogenous influences upon recent germline mutations. | Li X | Human mutation | 2000 | PMID: 11013449 |
The human factor IX gene as germline mutagen test: samples from Mainland China have the putatively endogenous pattern of mutation. | Liu JZ | Human mutation | 2000 | PMID: 10874302 |
Fast and efficient mutation detection method using multiplex PCR and cycle sequencing--application to haemophilia B. | Costa JM | Thrombosis and haemostasis | 2000 | PMID: 10739381 |
Factor IX gene analysis in 70 unrelated patients with haemophilia B: description of 13 new mutations. | Attali O | Thrombosis and haemostasis | 1999 | PMID: 10595634 |
Identification of twenty-one new mutations in the factor IX gene by SSCP analysis. | Montejo JM | Human mutation | 1999 | PMID: 10094553 |
Twenty-five novel mutations of the factor IX gene in haemophilia B. | Wulff K | Human mutation | 1995 | PMID: 8680410 |
Heteroduplex screening for molecular defects in factor IX genes from haemophilia B families. | Chen SH | British journal of haematology | 1995 | PMID: 7873393 |
First report on UK database of haemophilia B mutations and pedigrees. UK Haemophilia Centres. | Saad S | Thrombosis and haemostasis | 1994 | PMID: 8091381 |
Characterization of factor IX defects in hemophilia B patients. | Thompson AR | Methods in enzymology | 1993 | PMID: 8412791 |
Recurrent mutations in the factor IX gene: founder effect or repeat de novo events. Investigation of the German haemophilia B population and review of de novo mutations. | Knobloch O | Human genetics | 1993 | PMID: 8365725 |
Hemophilia B carrier determination based on family-specific mutation detection by DNA single-strand conformation analysis. | Poon MC | The Journal of laboratory and clinical medicine | 1993 | PMID: 8320491 |
The pattern of spontaneous germ-line mutation: relative rates of mutation at or near CpG dinucleotides in the factor IX gene. | Bottema CD | Human genetics | 1993 | PMID: 8314564 |
Haplotype analysis of identical factor IX mutants using PCR. | Green PM | Thrombosis and haemostasis | 1992 | PMID: 1615486 |
Identification of haemophilia B patients with mutations in the two calcium binding domains of factor IX: importance of a beta-OH Asp 64----Asn change. | Winship PR | British journal of haematology | 1991 | PMID: 1998585 |
The incidence and distribution of CpG----TpG transitions in the coagulation factor IX gene. A fresh look at CpG mutational hotspots. | Green PM | Nucleic acids research | 1990 | PMID: 1972560 |
Factor IX Cardiff: a variant factor IX protein that shows abnormal activation is caused by an arginine to cysteine substitution at position 145. | Liddell MB | British journal of haematology | 1989 | PMID: 2775660 |
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Text-mined citations for rs137852237 ...
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.