ClinVar Genomic variation as it relates to human health
NM_021871.4(FGA):c.104G>A (p.Arg35His)
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.
(10)
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
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_021871.4(FGA):c.104G>A (p.Arg35His)
Variation ID: 16404 Accession: VCV000016404.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q31.3 4: 154589513 (GRCh38) [ NCBI UCSC ] 4: 155510665 (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 Nov 9, 2018 Oct 8, 2024 Apr 9, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_021871.4:c.104G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_068657.1:p.Arg35His missense NM_000508.5:c.104G>A NP_000499.1:p.Arg35His missense NC_000004.12:g.154589513C>T NC_000004.11:g.155510665C>T NG_008832.1:g.6233G>A LRG_557:g.6233G>A LRG_557t1:c.104G>A LRG_557p1:p.Arg35His LRG_557t2:c.104G>A P02671:p.Arg35His - Protein change
- R35H
- Other names
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R16H
FIBRINOGEN AMIENS 1
FIBRINOGEN AMIENS 2
FIBRINOGEN BERGAMO 3
FIBRINOGEN BERN 2
FIBRINOGEN BICETRE 1
FIBRINOGEN BIRMINGHAM 1
FIBRINOGEN CHAPEL HILL 2
FIBRINOGEN CLERMONT-FERRAND 1
FIBRINOGEN GIESSEN 1
FIBRINOGEN LEITCHFIELD
FIBRINOGEN LONG BEACH 1
FIBRINOGEN LOUISVILLE 1
FIBRINOGEN MANCHESTER 1
FIBRINOGEN PARIS 6
FIBRINOGEN PETOSKEY 1
FIBRINOGEN SEATTLE 2
FIBRINOGEN SHEFFIELD 2
FIBRINOGEN SYDNEY 1
FIBRINOGEN SYDNEY 2
FIBRINOGEN WHITE MARSH 1
Fibrinogen Petoskey
- Canonical SPDI
- NC_000004.12:154589512: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
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
- 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. |
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| FGA | - | - |
GRCh38 GRCh37 |
222 | 254 | |
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 (1) |
no assertion criteria provided
|
Jul 1, 1989 | RCV000030941.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 1, 2019 | RCV000851971.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 1, 2019 | RCV000851581.1 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 9, 2024 | RCV001509236.12 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 29, 2022 | RCV002228034.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 20, 2022 | RCV002476987.1 | |
|
FGA-related disorder
|
Pathogenic (1) |
no assertion criteria provided
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May 28, 2024 | RCV004532379.2 |
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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|---|---|---|---|---|---|
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Pathogenic
(Feb 01, 2019)
|
criteria provided, single submitter
Method: research
|
Hypofibrinogenemia
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Study: ThromboGenomics
Accession: SCV000899295.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Observation 1: Observation 2:
Ethnicity/Population group: European
Observation 3:
Sex: female
Ethnicity/Population group: European
Observation 4:
Sex: female
Ethnicity/Population group: South-Asian,European
Observation 5:
Sex: female
Ethnicity/Population group: European
Observation 6:
Sex: male
Ethnicity/Population group: European
Observation 7:
Sex: male
Ethnicity/Population group: South-Asian
Observation 8:
Sex: male
Ethnicity/Population group: European
Observation 9:
Sex: male
Ethnicity/Population group: European
Observation 10:
Sex: male
Ethnicity/Population group: European
Observation 11:
Sex: female
Ethnicity/Population group: European
Observation 12:
Sex: male
Ethnicity/Population group: European
|
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Pathogenic
(Feb 01, 2019)
|
criteria provided, single submitter
Method: research
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Abnormal bleeding
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Study: ThromboGenomics
Accession: SCV000899410.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Sex: female
Ethnicity/Population group: European
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Pathogenic
(Jul 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial dysfibrinogenemia
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV002570398.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
This FGA missense variant has been identified in the heterozygous state in multiple individuals with congenital dysfibrinogenemia, and is also reported in individuals with FGA-related … (more)
This FGA missense variant has been identified in the heterozygous state in multiple individuals with congenital dysfibrinogenemia, and is also reported in individuals with FGA-related congenital fibrinogen defects due to biallelic variants. This variant (rs121909607) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 4/282670 total alleles; 0.0014%; no homozygotes). It has been reported in ClinVar7 (Variation ID 16404). Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is evolutionarily conserved across all species assessed. Functional studies support that this missense change impacts protein function. We consider c.104G>A in FGA to be pathogenic. (less)
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Pathogenic
(Apr 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial visceral amyloidosis, Ostertag type
Congenital afibrinogenemia Familial dysfibrinogenemia
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002804033.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Aug 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial dysfibrinogenemia
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175401.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The FGA c.104G>A variant is classified as Pathogenic (PS1, PS4, PM1, PM2) The FGA c.104G>A variant is a single nucleotide change in exon 2/6 of … (more)
The FGA c.104G>A variant is classified as Pathogenic (PS1, PS4, PM1, PM2) The FGA c.104G>A variant is a single nucleotide change in exon 2/6 of the FGA gene, which is predicted to change the amino acid arginine at position 35 in the protein to histidine. The variant has been reported in probands with a clinical presentation of MIM: 616004 (PS4). The variant is rare in population databases (gnomAD allele frequency = 0.0013%; 2 het and 0 hom in 152172 sequenced alleles; highest frequency = 0.0024%, African/African American population) (PM2). Detected in 7x patients with disease in PMID 31064749. This variant is located in a conserved region (PM1). (PMID:34275736) This variant results in the same amino acid change as a previously established variant (PS1). The variant has been reported in dbSNP (rs121909607) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 16404). It has not been reported in HGMD. (less)
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Pathogenic
(Apr 09, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001874102.6
First in ClinVar: Sep 19, 2021 Last updated: Sep 29, 2024 |
Comment:
Published functional studies suggest a damaging effect: impaired thrombin polymerization, reduced fibrinogen clottability, reduced fibrinolysis velocity, and delayed release of fibrinopeptide A (PMID: 6830702, 22967385, … (more)
Published functional studies suggest a damaging effect: impaired thrombin polymerization, reduced fibrinogen clottability, reduced fibrinolysis velocity, and delayed release of fibrinopeptide A (PMID: 6830702, 22967385, 22880226); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as R16H using alternate nomenclature; This variant is associated with the following publications: (PMID: 32877852, 33822462, 33443927, 34275736, 32939696, 23962069, 22880226, 22967385, 6830702, 27684817, 6191801, 2738154, 9391726, 25320241, 26577257, 29070135, 29869737, 30856382, 31314131, 30332696, 32166693, 30349899, 2379562, 35949040, 35975558, 31064749, 3618591, 34455742, 7298640, 22169505) (less)
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Pathogenic
(Apr 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial dysfibrinogenemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002511863.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
Variant summary: FGA c.104G>A (p.Arg35His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: FGA c.104G>A (p.Arg35His) results in a non-conservative amino acid change in 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 1.2e-05 in 251286 control chromosomes (gnomAD). c.104G>A has been reported in the literature in multiple individuals affected with Congenital Dysfibrinogenemia (e.g. Simurda_2020, Szanto_2021, Zhou_2021), including at least one homozygote (Alving_1987). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 04, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715840.3
First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024 |
Comment:
PM1, PM2, PM5, PS3, PS4_moderate
Number of individuals with the variant: 17
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Pathogenic
(Jul 01, 1989)
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no assertion criteria provided
Method: literature only
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FIBRINOGEN PETOSKEY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000038124.5
First in ClinVar: Apr 04, 2013 Last updated: Nov 09, 2018 |
Comment on evidence:
Fibrinogen Petoskey-1 has also been called fibrinogen Amiens-1, Amiens-2, Bergamo-3, Bern-2, Bicetre-1, Birmingham-1, Chapel Hill-2, Clermont-Ferrand-1, Giessen-1, Leitchfield, Long Beach-1, Louisville-1, Manchester-1, Paris-6, Petoskey-1, Seattle-2, … (more)
Fibrinogen Petoskey-1 has also been called fibrinogen Amiens-1, Amiens-2, Bergamo-3, Bern-2, Bicetre-1, Birmingham-1, Chapel Hill-2, Clermont-Ferrand-1, Giessen-1, Leitchfield, Long Beach-1, Louisville-1, Manchester-1, Paris-6, Petoskey-1, Seattle-2, Sheffield-2, Sydney-1, Sydney-2, and White Marsh-1. In fibrinogen Petoskey (named for Petoskey, Michigan, the site of the hospital where the blood samples were collected), Higgins and Shafer (1981) detected replacement of arg-A(alpha)16 by a histidyl residue (R16H). In an abnormal fibrinogen associated with excessive postpartum bleeding and called fibrinogen White Marsh for the Virginia town of the patient's residence, Qureshi et al. (1983) also found the R16H mutation in the alpha chain. Carrell et al. (1983) gave the name fibrinogen Chapel Hill to a fibrinogen variant associated with thrombotic disease. Fibrinogen Manchester also exhibits the R16H mutation. Southan et al. (1985) found that platelet fibrinogen expresses the heterozygous R16H phenotype, thus supporting the view that the A-alpha chains of platelet and plasma fibrinogen are produced by a single genetic locus. Alving and Henschen (1987) reported that a patient homozygous for fibrinogen Giessen I had a substitution of histidine for arginine at position 16. Although this patient had had excessive postpartum bleeding, she had normal hemostasis throughout several minor surgical procedures and during hysterectomy. Reber et al. (1987) described 2 fibrinogen variants in which there was a substitution for arginine-16 in the alpha chain by histidine in one and by cysteine in the other; these were designated fibrinogen Bergamo III and fibrinogen Torino (134820.0003), respectively. See also Galanakis et al. (1983), Ebert et al. (1986), and Siebenlist et al. (1988). According to Galanakis (1993), the R16H mutation had been identified in 22 unrelated families, making it the most frequent form of dysfibrinogenemia. Together with R16C, it represented the majority of the mutations characterized, 37 out of 63. (less)
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Pathogenic
(May 28, 2024)
|
no assertion criteria provided
Method: clinical testing
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FGA-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004117662.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The FGA c.104G>A variant is predicted to result in the amino acid substitution p.Arg35His. This variant, also referred to as p.Arg16His using legacy nomenclature, has … (more)
The FGA c.104G>A variant is predicted to result in the amino acid substitution p.Arg35His. This variant, also referred to as p.Arg16His using legacy nomenclature, has been reported in many patients to be causative for autosomal dominant congenital dysfibrinogenemia (Casini et al. 2015. PubMed ID: 25320241; Siebenlist et al. 1988. PubMed ID: 3345340; Smith et al. 2018. PubMed ID: 30349899; Shapiro et al. 2013. PubMed ID: 23061815). Other missense variants affecting this amino acid (p.Arg35Cys, p.Arg35Ser, p.Arg35Pro) have also been reported in patients with dysfibrinogenemia, suggesting p.Arg35 is important for proper FGA protein function (Miesbach et al. 2010. PubMed ID: 19923982; Shapiro et al. 2013. PubMed ID: 23061815). This variant is reported in 0.0031% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
|
Citation text
Qureshi, G. D., Evans, H. J., Vennart, R. M., Magnant, J. P., Sabau, J. M., Willoughby, J. B., Koehn, J. A. Fibrinogen White Marsh--a new human fibrinogen variant with alpha chain defect. (Abstract) Clin. Res. 31: 321A-only, 1983.
Citation text
Ebert, R. F. Index of Variant Human Fibrinogens. Rockville, Md.: Privately published (pub.) 1990.
Citation text
Galanakis, D. K., Henschen, A., Keeling, M., Kehl, M., Dismore, R., Peerschke, E. I. Fibrinogen Louisville: an A-alpha-16-arg-to-his defect that forms no hybrid molecules in heterozygous individuals and inhibits aggregation of normal fibrin monomers. Ann. N.Y. Acad. Sci. 408: 644-648, 1983.
Comment:
This FGA missense variant has been identified in the heterozygous state in multiple individuals with congenital dysfibrinogenemia, and is also reported in individuals with FGA-related congenital fibrinogen defects due to biallelic variants. This variant (rs121909607) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 4/282670 total alleles; 0.0014%; no homozygotes). It has been reported in ClinVar7 (Variation ID 16404). Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is evolutionarily conserved across all species assessed. Functional studies support that this missense change impacts protein function. We consider c.104G>A in FGA to be pathogenic.
Comment:
The FGA c.104G>A variant is classified as Pathogenic (PS1, PS4, PM1, PM2) The FGA c.104G>A variant is a single nucleotide change in exon 2/6 of the FGA gene, which is predicted to change the amino acid arginine at position 35 in the protein to histidine. The variant has been reported in probands with a clinical presentation of MIM: 616004 (PS4). The variant is rare in population databases (gnomAD allele frequency = 0.0013%; 2 het and 0 hom in 152172 sequenced alleles; highest frequency = 0.0024%, African/African American population) (PM2). Detected in 7x patients with disease in PMID 31064749. This variant is located in a conserved region (PM1). (PMID:34275736) This variant results in the same amino acid change as a previously established variant (PS1). The variant has been reported in dbSNP (rs121909607) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 16404). It has not been reported in HGMD.
Comment:
Published functional studies suggest a damaging effect: impaired thrombin polymerization, reduced fibrinogen clottability, reduced fibrinolysis velocity, and delayed release of fibrinopeptide A (PMID: 6830702, 22967385, 22880226); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as R16H using alternate nomenclature; This variant is associated with the following publications: (PMID: 32877852, 33822462, 33443927, 34275736, 32939696, 23962069, 22880226, 22967385, 6830702, 27684817, 6191801, 2738154, 9391726, 25320241, 26577257, 29070135, 29869737, 30856382, 31314131, 30332696, 32166693, 30349899, 2379562, 35949040, 35975558, 31064749, 3618591, 34455742, 7298640, 22169505)
Comment:
Variant summary: FGA c.104G>A (p.Arg35His) results in a non-conservative amino acid change in 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 1.2e-05 in 251286 control chromosomes (gnomAD). c.104G>A has been reported in the literature in multiple individuals affected with Congenital Dysfibrinogenemia (e.g. Simurda_2020, Szanto_2021, Zhou_2021), including at least one homozygote (Alving_1987). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
PM1, PM2, PM5, PS3, PS4_moderate
Comment:
The FGA c.104G>A variant is predicted to result in the amino acid substitution p.Arg35His. This variant, also referred to as p.Arg16His using legacy nomenclature, has been reported in many patients to be causative for autosomal dominant congenital dysfibrinogenemia (Casini et al. 2015. PubMed ID: 25320241; Siebenlist et al. 1988. PubMed ID: 3345340; Smith et al. 2018. PubMed ID: 30349899; Shapiro et al. 2013. PubMed ID: 23061815). Other missense variants affecting this amino acid (p.Arg35Cys, p.Arg35Ser, p.Arg35Pro) have also been reported in patients with dysfibrinogenemia, suggesting p.Arg35 is important for proper FGA protein function (Miesbach et al. 2010. PubMed ID: 19923982; Shapiro et al. 2013. PubMed ID: 23061815). This variant is reported in 0.0031% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted 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:
This FGA missense variant has been identified in the heterozygous state in multiple individuals with congenital dysfibrinogenemia, and is also reported in individuals with FGA-related congenital fibrinogen defects due to biallelic variants. This variant (rs121909607) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 4/282670 total alleles; 0.0014%; no homozygotes). It has been reported in ClinVar7 (Variation ID 16404). Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is evolutionarily conserved across all species assessed. Functional studies support that this missense change impacts protein function. We consider c.104G>A in FGA to be pathogenic.
Comment:
The FGA c.104G>A variant is classified as Pathogenic (PS1, PS4, PM1, PM2) The FGA c.104G>A variant is a single nucleotide change in exon 2/6 of the FGA gene, which is predicted to change the amino acid arginine at position 35 in the protein to histidine. The variant has been reported in probands with a clinical presentation of MIM: 616004 (PS4). The variant is rare in population databases (gnomAD allele frequency = 0.0013%; 2 het and 0 hom in 152172 sequenced alleles; highest frequency = 0.0024%, African/African American population) (PM2). Detected in 7x patients with disease in PMID 31064749. This variant is located in a conserved region (PM1). (PMID:34275736) This variant results in the same amino acid change as a previously established variant (PS1). The variant has been reported in dbSNP (rs121909607) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 16404). It has not been reported in HGMD.
Comment:
Published functional studies suggest a damaging effect: impaired thrombin polymerization, reduced fibrinogen clottability, reduced fibrinolysis velocity, and delayed release of fibrinopeptide A (PMID: 6830702, 22967385, 22880226); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as R16H using alternate nomenclature; This variant is associated with the following publications: (PMID: 32877852, 33822462, 33443927, 34275736, 32939696, 23962069, 22880226, 22967385, 6830702, 27684817, 6191801, 2738154, 9391726, 25320241, 26577257, 29070135, 29869737, 30856382, 31314131, 30332696, 32166693, 30349899, 2379562, 35949040, 35975558, 31064749, 3618591, 34455742, 7298640, 22169505)
Comment:
Variant summary: FGA c.104G>A (p.Arg35His) results in a non-conservative amino acid change in 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 1.2e-05 in 251286 control chromosomes (gnomAD). c.104G>A has been reported in the literature in multiple individuals affected with Congenital Dysfibrinogenemia (e.g. Simurda_2020, Szanto_2021, Zhou_2021), including at least one homozygote (Alving_1987). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
PM1, PM2, PM5, PS3, PS4_moderate
Comment:
The FGA c.104G>A variant is predicted to result in the amino acid substitution p.Arg35His. This variant, also referred to as p.Arg16His using legacy nomenclature, has been reported in many patients to be causative for autosomal dominant congenital dysfibrinogenemia (Casini et al. 2015. PubMed ID: 25320241; Siebenlist et al. 1988. PubMed ID: 3345340; Smith et al. 2018. PubMed ID: 30349899; Shapiro et al. 2013. PubMed ID: 23061815). Other missense variants affecting this amino acid (p.Arg35Cys, p.Arg35Ser, p.Arg35Pro) have also been reported in patients with dysfibrinogenemia, suggesting p.Arg35 is important for proper FGA protein function (Miesbach et al. 2010. PubMed ID: 19923982; Shapiro et al. 2013. PubMed ID: 23061815). This variant is reported in 0.0031% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical and molecular characterization of Iranian patients with congenital fibrinogen disorders. | Mohsenian S | Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis | 2021 | PMID: 34275736 |
| Whole Blood Thromboelastometry by ROTEM and Thrombin Generation by Genesia According to the Genotype and Clinical Phenotype in Congenital Fibrinogen Disorders. | Szanto T | International journal of molecular sciences | 2021 | PMID: 33668986 |
| Identification and characterization of novel mutations in Chinese patients with congenital fibrinogen disorders. | Zhou P | Blood cells, molecules & diseases | 2021 | PMID: 32877852 |
| Comparison of clinical phenotype with genetic and laboratory results in 31 patients with congenital dysfibrinogenemia in northern Slovakia. | Simurda T | International journal of hematology | 2020 | PMID: 32166693 |
| Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. | Downes K | Blood | 2019 | PMID: 31064749 |
| Mutational Epidemiology of Congenital Fibrinogen Disorders. | Casini A | Thrombosis and haemostasis | 2018 | PMID: 30332696 |
| Fibrin Formation, Structure and Properties. | Weisel JW | Sub-cellular biochemistry | 2017 | PMID: 28101869 |
| Three cases of congenital dysfibrinogenemia in unrelated Chinese families: heterozygous missense mutation in fibrinogen alpha chain Argl6His. | Luo M | Medicine | 2016 | PMID: 27684817 |
| Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management. | Casini A | Journal of thrombosis and haemostasis : JTH | 2015 | PMID: 25816717 |
| [Functional analysis for dysfibrinogenemias, Toyama and Adachi, which have a mutation of Aalpha16Arg-->His (CGT-->CAT) with aberrant fibrinopeptide A release]. | Soya K | Rinsho byori. The Japanese journal of clinical pathology | 2012 | PMID: 22880226 |
| Homophenotypic Aalpha R16H fibrinogen (Kingsport): uniquely altered polymerization associated with slower fibrinopeptide A than fibrinopeptide B release. | Galanakis DK | Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis | 2007 | PMID: 17982313 |
| Fibrinogen Stony Brook, a heterozygous A alpha 16Arg----Cys dysfibrinogenemia. Evaluation of diminished platelet aggregation support and of enhanced inhibition of fibrin assembly. | Galanakis DK | The Journal of clinical investigation | 1989 | PMID: 2738154 |
| Fibrinogen Birmingham: a heterozygous dysfibrinogenemia (A alpha 16 Arg----His) containing heterodimeric molecules. | Siebenlist KR | Blood | 1988 | PMID: 3345340 |
| Fibrinogen giessen I: a congenital homozygously expressed dysfibrinogenemia with A alpha 16 Arg----His substitution. | Alving BM | American journal of hematology | 1987 | PMID: 3618591 |
| Fibrinogen Bergamo III and fibrinogen Torino: two further variants with hereditary molecular defects in fibrinopeptide A. | Reber P | Thrombosis research | 1987 | PMID: 3590111 |
| Fibrinogen Manchester. Detection of a heterozygous phenotype in the intraplatelet pool. | Southan C | The Biochemical journal | 1985 | PMID: 4052020 |
| Hereditary dysfibrinogenemia in a patient with thrombotic disease. | Carrell N | Blood | 1983 | PMID: 6191801 |
| Fibrinogen Petoskey, a dysfibrinogenemia characterized by replacement of Arg-A alpha 16 by a histidyl residue. Evidence for thrombin-catalyzed hydrolysis at a histidyl residue. | Higgins DL | The Journal of biological chemistry | 1981 | PMID: 7298640 |
| Ebert, R. F. Index of Variant Human Fibrinogens. Rockville, Md.: Privately published (pub.) 1990. | - | - | - | - |
| Galanakis, D. K., Henschen, A., Keeling, M., Kehl, M., Dismore, R., Peerschke, E. I. Fibrinogen Louisville: an A-alpha-16-arg-to-his defect that forms no hybrid molecules in heterozygous individuals and inhibits aggregation of normal fibrin monomers. Ann. N.Y. Acad. Sci. 408: 644-648, 1983. | - | - | - | - |
| Qureshi, G. D., Evans, H. J., Vennart, R. M., Magnant, J. P., Sabau, J. M., Willoughby, J. B., Koehn, J. A. Fibrinogen White Marsh--a new human fibrinogen variant with alpha chain defect. (Abstract) Clin. Res. 31: 321A-only, 1983. | - | - | - | - |
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Text-mined citations for rs121909607 ...
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Record last updated Nov 10, 2024
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