VCV000420159.32 - ClinVar

NM_019616.4(F7):c.1025G>A (p.Arg342Gln)

Germline

Classification

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)

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; other

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_019616.4(F7):c.1025G>A (p.Arg342Gln)

Variation ID: 420159 Accession: VCV000420159.32

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q34 13: 113118698 (GRCh38) [ NCBI UCSC ] 13: 113773012 (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	Apr 4, 2013	Oct 20, 2024	Aug 15, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_019616.4:c.1025G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_062562.1:p.Arg342Gln	missense
NM_000131.4:c.1091G>A	NP_000122.1:p.Arg364Gln	missense
NM_001267554.2:c.839G>A	NP_001254483.1:p.Arg280Gln	missense
NR_051961.2:n.1109G>A		non-coding transcript variant
NC_000013.11:g.113118698G>A
NC_000013.10:g.113773012G>A
NG_009258.1:g.900G>A
NG_009262.1:g.17908G>A
LRG_548:g.900G>A
LRG_554:g.17908G>A
LRG_554t1:c.1091G>A	LRG_554p1:p.Arg364Gln

... more HGVS ... less HGVS

Protein change

R342Q, R364Q, R280Q

Other names

F7, ARG304GLN
R304Q
p.Arg364Gln

Canonical SPDI

NC_000013.11:113118697:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00240 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00040

Exome Aggregation Consortium (ExAC) 0.00052

The Genome Aggregation Database (gnomAD) 0.00118

Trans-Omics for Precision Medicine (TOPMed) 0.00129

1000 Genomes Project 0.00240

1000 Genomes Project 30x 0.00265

Links

ClinGen: CA7060219 LOVD 3: F7_000101 OMIM: 613878.0001 dbSNP: rs121964926 VarSome

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
Gene	OMIM	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.
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.
not provided	Pathogenic; other (4)	criteria provided, multiple submitters, no conflicts	Aug 15, 2024	RCV000479479.20
Factor VII deficiency	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 23, 2018	RCV000779130.6
Congenital factor VII deficiency	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 9, 2020	RCV003147479.5
F7-related disorder	Pathogenic (1)	no assertion criteria provided	Jul 23, 2024	RCV003419797.6
Factor VII Padua	Pathogenic (1)	no assertion criteria provided	Jul 1, 1992	RCV001843424.1
Congenital factor VII deficiency Myocardial infarction, susceptibility to	Pathogenic (1)	criteria provided, single submitter	Apr 12, 2022	RCV002496859.1

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.
other (Oct 30, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000857897.1 First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=F7 Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Oct 23, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Congenital factor VII deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000915625.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (7) PubMed: 21902896‚ 12903033‚ 25828579‚ 18282149‚ 20040857‚ 2070047‚ 20958793 Comment: The F7 c.1091G>A (p.Arg364Gln) missense variant, also commonly referred to in the literature as p.Arg304Gln or the "Pauda" variant, has been reported in at least … (more) The F7 c.1091G>A (p.Arg364Gln) missense variant, also commonly referred to in the literature as p.Arg304Gln or the "Pauda" variant, has been reported in at least eight studies in which it is identified in at least 70 individuals, including 11 clinically symptomatic homozygotes and two clinically symptomatic compound heterozygotes (Ding et al. 2003; Marty et al. 2008; Girolami et al. 2011; Rabelo et al. 2015). The p.Arg364Gln variant has also been reported in at least 19 clinically asymptomatic homozygotes with lower factor VII activity than wildtype (O'Brien et al. 1991; Girolami et al. 2011; Rabelo et al. 2015). The variant is present at a frequency of 0.00908 in the African population of the 1000 Genomes Project. This allele frequency is high but may be consistent with disease prevalence and the fact that many individuals with factor VII deficiency are clinically asymptomatic. Girolami et al. (2011) found the mean levels of activated FVII in six homozygotes to be significantly lower than the activated FVII levels in 21 normal controls. Further, the variant was associated with reduced factor VII activity when assayed with rabbit brain thromboplastin, however, the activity levels varied between the use of human placenta, recombinant human or ox-brain thromboplastin (O'Brien et al. 1991; Kirkel et al. 2010; Girolami et al. 2011; Girolami et al. 2011; Rabelo et al. 2015). Based on the collective evidence, the p.Arg364Gln variant is classified as a pathogenic risk factor for factor VII deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Jul 12, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Factor VII deficiency Affected status: unknown Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Accession: SCV001448741.1 First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020	Number of individuals with the variant: 1 Sex: female
Pathogenic (Apr 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital factor VII deficiency Myocardial infarction, susceptibility to Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002812402.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital factor VII deficiency Affected status: yes Allele origin: germline	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology Accession: SCV004013121.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 Comment: Submitted to the GoldVariant database by Kathleen Freson, Center for Molecular and Vascular Biology	Clinical Features: bleeding (present)
Pathogenic (Jan 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004224439.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Comment: PM3_strong, PM5, PS3, PS4_moderate Number of individuals with the variant: 9
Likely pathogenic (Oct 09, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital factor VII deficiency Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002024556.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Aug 15, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000568816.8 First in ClinVar: Apr 27, 2017 Last updated: Sep 29, 2024	Comment: Observed in apparent homozygous state in multiple unrelated patients in published literature and not observed in homozygous state in controls (PMID: 20958793, 25828579); Published studies … (more) Observed in apparent homozygous state in multiple unrelated patients in published literature and not observed in homozygous state in controls (PMID: 20958793, 25828579); Published studies demonstrate most individuals exhibit prolonged prothrombin times (PT) and F7 activity below 10% using rabbit brain thromboplastin, but normal PT and F7 activity using ox brain thromboplastin and intermediate values with human brain thromboplastin, while purified FVII protein from one individual homozygous for R364Q exhibited no detectable FVII clotting activity (PMID: 2070047, 20040857); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as R304Q and F7-Padua; This variant is associated with the following publications: (PMID: 31589614, 8242057, 8043443, 22995991, 18976247, 8883260, 15590402, 34598035, 32472540, 34342048, 21902896, 24711753, 12903033, 11313743, 1634227, 15970722, 10959697, 22873696, 20040857, 25828579, 26105150, 25863091, 35802509, 36760778, 36719811, 34426522, 2070047, 20958793, 38202056) (less)
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004135698.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: F7: PS4, PM3, PM5, PM2:Supporting, PS3:Supporting Number of individuals with the variant: 1
Pathogenic (Jul 01, 1992)	no assertion criteria provided Method: literature only	FACTOR VII PADUA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033088.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (3) PubMed: 2070047‚ 1634227‚ 6812354 Comment on evidence: In a 47-year-old man with no clinical bleeding tendency but with undetectable plasma factor VII activity when tested in a 1-stage assay using rabbit brain … (more) In a 47-year-old man with no clinical bleeding tendency but with undetectable plasma factor VII activity when tested in a 1-stage assay using rabbit brain tissue factor, O'Brien et al. (1991) identified a heterozygous G-to-A transition in the F7 gene, resulting in an arg304-to-gln (R304Q) substitution. Plasma from the patient showed normal factor VII antigen levels. Residue arg304 is homologous to arg333 of factor IX, and an arg333-to-gln mutation in F9 (300746.0056) has been identified in patients with severe hemophilia B (306900) in whom there is synthesis and expression of the factor IX protein. Marchetti et al. (1992) identified a heterozygous R304Q substitution in the F7 gene as the basis of abnormal factor VII Padua, described by Girolami et al. (1982) in persons originating from the Piave River valley in northeastern Italy. The individuals described by Girolami et al. (1982) were asymptomatic, but presented a mild prolongation of prothrombin time. Factor VII activity varied between 45% and 61% of normal, but factor VII cross-reacting material was normal. A good negative correlation was found between factor VII level and prothrombin times. (less)
Pathogenic (Jul 23, 2024)	no assertion criteria provided Method: clinical testing	F7-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004115092.2 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The F7 c.1091G>A variant is predicted to result in the amino acid substitution p.Arg364Gln. This variant is also described using legacy nomenclature as p.Arg304Gln, has … (more) The F7 c.1091G>A variant is predicted to result in the amino acid substitution p.Arg364Gln. This variant is also described using legacy nomenclature as p.Arg304Gln, has been reported to be causative for autosomal recessive factor VII deficiency in several patients with varying clinical phenotypes ranging from asymptomatic to mild bleeding or severe bleeding after trauma (Girolami et al. 2011. PubMed ID: 21902896; Kirkel et al. 2010. PubMed ID: 20040857; O’Brien et al. 1991. PubMed ID: 2070047). Most patients with the p.Arg364Gln variant showed prolonged prothrombin times (PT); however, PT results using F7 protein with this variant are variable – ranging from severely reduced to normal – depending upon the source of substrate used for the biochemical test (O’Brien et al. 1991. PubMed ID: 2070047; Cristiani et al. 2013. PubMed ID: 24711753). The p.Arg364Gln substitution does not appear to alter F7 protein levels, rather, it appears to alter substrate binding (see for example O’Brien et al. 1991. PubMed ID: 2070047; Cristiani et al. 2013. PubMed ID: 24711753). Other substitutions of amino acid p.Arg364 have been reported in patients with Factor VII deficiency (e.g. p.Arg364Trp, Matsushita et al. 1994. PubMed ID: 8125953, Cristiani et al. 2013. PubMed ID: 24711753) suggesting that amino acid residue p.Arg364 is important for proper F7 protein function. Given all the evidence, we interpret c.1091G>A (p.Arg364Gln) as pathogenic. (less)
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Comment:

The F7 c.1091G>A (p.Arg364Gln) missense variant, also commonly referred to in the literature as p.Arg304Gln or the "Pauda" variant, has been reported in at least eight studies in which it is identified in at least 70 individuals, including 11 clinically symptomatic homozygotes and two clinically symptomatic compound heterozygotes (Ding et al. 2003; Marty et al. 2008; Girolami et al. 2011; Rabelo et al. 2015). The p.Arg364Gln variant has also been reported in at least 19 clinically asymptomatic homozygotes with lower factor VII activity than wildtype (O'Brien et al. 1991; Girolami et al. 2011; Rabelo et al. 2015). The variant is present at a frequency of 0.00908 in the African population of the 1000 Genomes Project. This allele frequency is high but may be consistent with disease prevalence and the fact that many individuals with factor VII deficiency are clinically asymptomatic. Girolami et al. (2011) found the mean levels of activated FVII in six homozygotes to be significantly lower than the activated FVII levels in 21 normal controls. Further, the variant was associated with reduced factor VII activity when assayed with rabbit brain thromboplastin, however, the activity levels varied between the use of human placenta, recombinant human or ox-brain thromboplastin (O'Brien et al. 1991; Kirkel et al. 2010; Girolami et al. 2011; Girolami et al. 2011; Rabelo et al. 2015). Based on the collective evidence, the p.Arg364Gln variant is classified as a pathogenic risk factor for factor VII deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

Observed in apparent homozygous state in multiple unrelated patients in published literature and not observed in homozygous state in controls (PMID: 20958793, 25828579); Published studies demonstrate most individuals exhibit prolonged prothrombin times (PT) and F7 activity below 10% using rabbit brain thromboplastin, but normal PT and F7 activity using ox brain thromboplastin and intermediate values with human brain thromboplastin, while purified FVII protein from one individual homozygous for R364Q exhibited no detectable FVII clotting activity (PMID: 2070047, 20040857); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as R304Q and F7-Padua; This variant is associated with the following publications: (PMID: 31589614, 8242057, 8043443, 22995991, 18976247, 8883260, 15590402, 34598035, 32472540, 34342048, 21902896, 24711753, 12903033, 11313743, 1634227, 15970722, 10959697, 22873696, 20040857, 25828579, 26105150, 25863091, 35802509, 36760778, 36719811, 34426522, 2070047, 20958793, 38202056)

Comment:

The F7 c.1091G>A variant is predicted to result in the amino acid substitution p.Arg364Gln. This variant is also described using legacy nomenclature as p.Arg304Gln, has been reported to be causative for autosomal recessive factor VII deficiency in several patients with varying clinical phenotypes ranging from asymptomatic to mild bleeding or severe bleeding after trauma (Girolami et al. 2011. PubMed ID: 21902896; Kirkel et al. 2010. PubMed ID: 20040857; O’Brien et al. 1991. PubMed ID: 2070047). Most patients with the p.Arg364Gln variant showed prolonged prothrombin times (PT); however, PT results using F7 protein with this variant are variable – ranging from severely reduced to normal – depending upon the source of substrate used for the biochemical test (O’Brien et al. 1991. PubMed ID: 2070047; Cristiani et al. 2013. PubMed ID: 24711753). The p.Arg364Gln substitution does not appear to alter F7 protein levels, rather, it appears to alter substrate binding (see for example O’Brien et al. 1991. PubMed ID: 2070047; Cristiani et al. 2013. PubMed ID: 24711753). Other substitutions of amino acid p.Arg364 have been reported in patients with Factor VII deficiency (e.g. p.Arg364Trp, Matsushita et al. 1994. PubMed ID: 8125953, Cristiani et al. 2013. PubMed ID: 24711753) suggesting that amino acid residue p.Arg364 is important for proper F7 protein function. Given all the evidence, we interpret c.1091G>A (p.Arg364Gln) 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The molecular basis of low activity levels of coagulation factor VII: a Brazilian cohort.	Rabelo FY	Haemophilia : the official journal of the World Federation of Hemophilia	2015	PMID: 25828579
Activated FVII levels in factor VII Padua (Arg304Gln) coagulation disorder and in true factor VII deficiency: a study in homozygotes and heterozygotes.	Girolami A	Hematology (Amsterdam, Netherlands)	2011	PMID: 21902896
Worldwide diffusion of FVII Arg304Gln coagulation defect (FVII Padua).	Girolami A	European journal of haematology	2011	PMID: 20958793
Asymptomatic factor VII deficiency: gene analysis and structure-function relationships.	Kirkel D	Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis	2010	PMID: 20040857
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
[Inherited coagulation factor VII deficiency caused by double heterozygotic mutations Arg304Gln and Arg304Trp].	Ding QL	Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics	2003	PMID: 12903033
Detection of two missense mutations and characterization of a repeat polymorphism in the factor VII gene (F7).	Marchetti G	Human genetics	1992	PMID: 1634227
Purification and characterization of factor VII 304-Gln: a variant molecule with reduced activity isolated from a clinically unaffected male.	O'Brien DP	Blood	1991	PMID: 2070047
Factor VII Padua defect: the heterozygote population.	Girolami A	Acta haematologica	1982	PMID: 6812354
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=F7	-	-	-	-

Text-mined citations for rs121964926 ...

These 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 20, 2024

ClinVar Genomic variation as it relates to human health

NM_019616.4(F7):c.1025G>A (p.Arg342Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121964926 ...