ClinVar Genomic variation as it relates to human health
NM_019616.4(F7):c.995C>T (p.Ala332Val)
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_019616.4(F7):c.995C>T (p.Ala332Val)
Variation ID: 12076 Accession: VCV000012076.55
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q34 13: 113118668 (GRCh38) [ NCBI UCSC ] 13: 113772982 (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 May 21, 2018 Oct 8, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_019616.4:c.995C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_062562.1:p.Ala332Val missense NM_000131.4:c.1061C>T NP_000122.1:p.Ala354Val missense NM_001267554.2:c.809C>T NP_001254483.1:p.Ala270Val missense NM_019616.3:c.995C>T NR_051961.2:n.1079C>T non-coding transcript variant NC_000013.11:g.113118668C>T NC_000013.10:g.113772982C>T NG_009258.1:g.870C>T NG_009262.1:g.17878C>T LRG_548:g.870C>T LRG_554:g.17878C>T LRG_554t1:c.1061C>T LRG_554p1:p.Ala354Val P08709:p.Ala354Val - Protein change
- A354V, A332V, A270V
- Other names
- F7, ALA294VAL
- A294V
- Canonical SPDI
- NC_000013.11:113118667: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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00026
The Genome Aggregation Database (gnomAD) 0.00038
The Genome Aggregation Database (gnomAD), exomes 0.00056
Exome Aggregation Consortium (ExAC) 0.00075
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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F7 | - | - |
GRCh38 GRCh37 |
255 | 394 |
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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 11, 2019 | RCV000012857.13 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 30, 2024 | RCV001091742.35 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2019 | RCV000851974.2 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 21, 2023 | RCV002243638.13 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 27, 2022 | RCV002496330.2 | |
F7-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Aug 13, 2024 | RCV004752703.1 |
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
(Feb 01, 2019)
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criteria provided, single submitter
Method: research
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Congenital factor VII deficiency
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Study: ThromboGenomics
Accession: SCV000899413.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Sex: male
Ethnicity/Population group: European
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Likely pathogenic
(Feb 01, 2019)
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criteria provided, single submitter
Method: research
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Abnormal bleeding
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Study: ThromboGenomics
Accession: SCV000899414.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Sex: female
Ethnicity/Population group: Other
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Likely pathogenic
(Sep 11, 2019)
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criteria provided, single submitter
Method: clinical testing
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Congenital factor VII deficiency
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368367.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP3,PP5.
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Pathogenic
(Sep 01, 2021)
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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: SCV001586999.3
First in ClinVar: May 10, 2021 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces alanine with valine at codon 354 of the F7 protein (p.Ala354Val). The alanine residue is moderately conserved and there is a … (more)
This sequence change replaces alanine with valine at codon 354 of the F7 protein (p.Ala354Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs36209567, ExAC 0.1%). This missense change has been observed in individuals with factor VII deficiency (PMID: 7919338, 7981691, 10862079, 15735798). It has also been observed to segregate with disease in related individuals. This variant is also known as Ala294Val. ClinVar contains an entry for this variant (Variation ID: 12076). 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 C0"). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Oct 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Congenital factor VII deficiency
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175609.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The F7 c.995C>T variant is classified as LIKELY PATHOGENIC (PM2_Supporting, PM1, PM3, PP4) The F7 c.995C>T variant is a single nucleotide substitution in exon 8/8 … (more)
The F7 c.995C>T variant is classified as LIKELY PATHOGENIC (PM2_Supporting, PM1, PM3, PP4) The F7 c.995C>T variant is a single nucleotide substitution in exon 8/8 of the F7 gene, which is predicted to change the alanine at position 332 in the protein to valine. This variant is in dbSNP (rs36209567) and is present in population databases at extremely low frequency (0.00002%, AR) (PM2_Supporting). The variant is in a functional domain (PM1). This variant has been reported as homozygous and compound heterozygous and was detected in trans in this patient with a likely pathogenic variant (PM3). The patient’s phenotype is highly specific for a disease with a single genetic aetiology (biochemical functional assay show low FVII activity) (PP4). (less)
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Pathogenic
(Aug 15, 2018)
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criteria provided, single submitter
Method: clinical testing
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Congenital factor VII deficiency
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915624.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The F7 c.1061C>T (p.Ala354Val) missense variant, previously known as p.Ala294Val, has been reported in more than seven studies in which it is found in a … (more)
The F7 c.1061C>T (p.Ala354Val) missense variant, previously known as p.Ala294Val, has been reported in more than seven studies in which it is found in a total of more than 97 alleles in individuals with factor VII deficiency, including 10 homozygotes and four compound heterozygotes (Bernardi et al. 1994; Wulff et al. 2000; Fromovich-Amit et al. 2004; Mariani et al. 2005; Marty et al. 2008; Branchini et al. 2012; Pavlova et al. 2015). Of note, this variant is also described in cis with a second variant, c.11128delC, in an additional 111 alleles in affected individuals, including 26 individuals homozygous for both variants. The p.Ala354Val variant was absent from 20 controls, but is reported at a frequency of 0.00128 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional analysis of FVII activity in the plasma of a homozygous individual carrying this variant and the second variant, c.11128delC, showed drastically reduced activity. In vivo studies of the p.Ala354Val variant identified decreased activation of FX by variant FVII protein; however, functional studies showed discordant results when evaluating alterations in the variant protein's interaction with activators and cofactors (Toso et al. 2002; Fromovich-Amit et al. 2004; Branchini et al. 2012). Based on the evidence, the p.Ala354Val variant is classified as pathogenic for factor VII deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely pathogenic
(Feb 25, 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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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002051598.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 11, 2022 |
Comment:
PS3, PM3_Supporting, PP3
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Likely pathogenic
(Apr 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Congenital factor VII deficiency
Myocardial infarction, susceptibility to
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002775852.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Congenital factor VII deficiency
Affected status: yes
Allele origin:
germline
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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002515630.3
First in ClinVar: May 21, 2022 Last updated: Jul 22, 2023
Comment:
Submitted to the GoldVariant database by Kathleen Freson, Center for Molecular and Vascular Biology
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Clinical Features:
Bleeding (present)
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Likely pathogenic
(Dec 14, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002573746.2
First in ClinVar: Sep 24, 2022 Last updated: Jan 26, 2024 |
Comment:
PP5, PM3, PS3
Number of individuals with the variant: 6
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Pathogenic
(Dec 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Congenital factor VII deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005087246.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with factor VII deficiency (MIM#227500) and myocardial infarction, decreased susceptibility to (MIM#608446). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Patients with the same genotype have been observed with phenotypes ranging from asymptomatic to symptomatic (PMID: 18976247). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (157 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools. (I) 0600 - Variant is located in the annotated trypsin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in many homozygote individuals, including individuals homozygote for this variant in cis with p.(Pro442Hisfs*32), and in compound heterozygote individuals, with reduced FVII activity. It has also been reported as pathogenic and likely pathogenic in ClinVar; including one VUS classification (PMID: 18976247). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jan 30, 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: SCV003840668.2
First in ClinVar: Mar 18, 2023 Last updated: Sep 29, 2024 |
Comment:
Identified in the homozygous state or with a pathogenic variant on the opposite allele in multiple unrelated patients in the literature (PMID: 15735798, 24533960); In … (more)
Identified in the homozygous state or with a pathogenic variant on the opposite allele in multiple unrelated patients in the literature (PMID: 15735798, 24533960); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as A294V; This variant is associated with the following publications: (PMID: 24533960, 31064749, 22180436, 7981691, 30431218, 31980526, 31589614, 29431110, 29618153, 33406812, 15735798, 35552711, 36944032, 25582404, 11931672, 18282149, 15456489, 7919338, 10862079) (less)
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Likely pathogenic
(Jan 01, 2023)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247947.24
First in ClinVar: May 12, 2020 Last updated: Oct 08, 2024 |
Comment:
F7: PS4, PM2, PS3:Moderate, PP4
Number of individuals with the variant: 2
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Pathogenic
(Jan 01, 2000)
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no assertion criteria provided
Method: literature only
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FACTOR VII DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033098.3
First in ClinVar: Apr 04, 2013 Last updated: May 21, 2018 |
Comment on evidence:
In 2 sibs with partial factor VII deficiency (227500), Bernardi et al. (1994) identified compound heterozygosity for 2 mutations in the F7 gene: a 10798C-T … (more)
In 2 sibs with partial factor VII deficiency (227500), Bernardi et al. (1994) identified compound heterozygosity for 2 mutations in the F7 gene: a 10798C-T transition in exon 8, resulting in an ala294-to-val (A294V) substitution, and a 17-bp deletion leading to a frameshift and a premature termination at codon 255 (613878.0011). Factor VII antigen levels were 38% and 25% of normal, and activity levels were 18% and 7% of normal, respectively. In a study in Germany, Wulff and Herrmann (2000) found that the missense mutation A294V and the double mutation A294V/11128delC (613878.0012) were by far the most prevalent. (less)
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Pathogenic
(Aug 13, 2024)
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no assertion criteria provided
Method: clinical testing
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F7-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005358144.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The F7 c.1061C>T variant is predicted to result in the amino acid substitution p.Ala354Val. This variant, previously described as p.Ala294Val using legacy nomenclature, has been … (more)
The F7 c.1061C>T variant is predicted to result in the amino acid substitution p.Ala354Val. This variant, previously described as p.Ala294Val using legacy nomenclature, has been reported in many patients to be causative for recessive Factor VII Deficiency (see, for example, Wulff et al. 2000. PubMed ID: 10862079; Millar et al. 2000. PubMed ID: 11129332; Mariani et al. 2005. PubMed ID: 15735798; http://F7-db.eahad.org/). This variant is reported in 0.10% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
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Uncertain significance
(Dec 10, 2020)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Older and outlier claim with insufficient supporting evidence
Source: ClinGen
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Congenital factor VII deficiency
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003832330.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. | Downes K | Blood | 2019 | PMID: 31064749 |
Congenital combined deficiency of coagulation factors VII and X--different genetic mechanisms. | Pavlova A | Haemophilia : the official journal of the World Federation of Hemophilia | 2015 | PMID: 25582404 |
Natural and engineered carboxy-terminal variants: decreased secretion and gain-of-function result in asymptomatic coagulation factor VII deficiency. | Branchini A | Haematologica | 2012 | PMID: 22180436 |
Factor VII deficiency: clinical manifestation of 717 subjects from Europe and Latin America with mutations in the factor 7 gene. | Herrmann FH | Haemophilia : the official journal of the World Federation of Hemophilia | 2009 | PMID: 18976247 |
The paradoxical association between inherited factor VII deficiency and venous thrombosis. | Marty S | Haemophilia : the official journal of the World Federation of Hemophilia | 2008 | PMID: 18282149 |
Clinical phenotypes and factor VII genotype in congenital factor VII deficiency. | Mariani G | Thrombosis and haemostasis | 2005 | PMID: 15735798 |
Characterization of mutations causing factor VII deficiency in 61 unrelated Israeli patients. | Fromovich-Amit Y | Journal of thrombosis and haemostasis : JTH | 2004 | PMID: 15456489 |
A frequent human coagulation Factor VII mutation (A294V, c152) in loop 140s affects the interaction with activators, tissue factor and substrates. | Toso R | The Biochemical journal | 2002 | PMID: 11931672 |
Twenty two novel mutations of the factor VII gene in factor VII deficiency. | Wulff K | Human mutation | 2000 | PMID: 10862079 |
Topologically equivalent mutations causing dysfunctional coagulation factors VII (294Ala-->Val) and X (334Ser-->Pro). | Bernardi F | Human molecular genetics | 1994 | PMID: 7981691 |
Molecular analysis of Polish patients with factor VII deficiency. | Arbini AA | Blood | 1994 | PMID: 7919338 |
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Text-mined citations for rs36209567 ...
HelpRecord last updated Oct 13, 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.