VCV000016362.10 - ClinVar

NM_021870.2(FGG):c.902G>A (p.Arg301His)

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.

(8)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_021870.2(FGG):c.902G>A (p.Arg301His)

Variation ID: 16362 Accession: VCV000016362.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q32.1 4: 154606932 (GRCh38) [ NCBI UCSC ] 4: 155528084 (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	Sep 22, 2014	Sep 29, 2024	Jul 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_021870.3:c.902G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_068656.2:p.Arg301His	missense
NM_000509.4:c.902G>A
NM_000509.6:c.902G>A	NP_000500.2:p.Arg301His	missense
NC_000004.12:g.154606932C>T
NC_000004.11:g.155528084C>T
NG_008834.1:g.10819G>A
LRG_585:g.10819G>A
LRG_585t1:c.902G>A	LRG_585p1:p.Arg301His
LRG_585t2:c.902G>A	LRG_585p2:p.Arg301His
	P02679:p.Arg301His

... more HGVS ... less HGVS

Protein change

R301H

Other names

R275H
FIBRINOGEN ESSEN 1
FIBRINOGEN HAIFA 1
FIBRINOGEN PERUGIA 1
FIBRINOGEN SAGA 1
FIBRINOGEN OSAKA 3

Canonical SPDI

NC_000004.12:154606931:C:T

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.

0.00020 (T)

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

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA126391 UniProtKB: P02679#VAR_002410 OMIM: 134850.0002 dbSNP: rs121913088 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.
FGG		-	-	GRCh38 GRCh37	149	183

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.
FIBRINOGEN HAIFA 1	other (1)	no assertion criteria provided	Sep 19, 2014	RCV000017777.12
Hypofibrinogenemia	Pathogenic (1)	criteria provided, single submitter	Feb 1, 2019	RCV000851952.9
Familial dysfibrinogenemia	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	May 21, 2024	RCV002225266.12
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 23, 2024	RCV003151729.10

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.
Pathogenic (Feb 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hypofibrinogenemia Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Study: ThromboGenomics Accession: SCV000899374.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019	Publications: PubMed (1) PubMed: 31064749 Observation 1: Sex: male Ethnicity/Population group: European Observation 2: Sex: male Ethnicity/Population group: European Observation 3: Sex: female Ethnicity/Population group: Other
Pathogenic (Jul 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial dysfibrinogenemia Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004041247.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023
Pathogenic (Jul 23, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003840805.2 First in ClinVar: Mar 18, 2023 Last updated: Sep 29, 2024	Comment: Published functional studies suggest a damaging effect (PMID: 20508898); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.R275H; This variant … (more) Published functional studies suggest a damaging effect (PMID: 20508898); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.R275H; This variant is associated with the following publications: (PMID: 23683413, 30512152, 36964972, 34455742, 35063457, 7654933, 19132250, 3563970, 1455400, 2958955, 17604827, 30349899, 20546853, 30856382, 34355501, 29351094, 32877852, 20508898, 31064749) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial dysfibrinogenemia Affected status: yes Allele origin: unknown	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology Accession: SCV002505347.1 First in ClinVar: Apr 30, 2022 Last updated: Apr 30, 2022 Comment: GoldVariant submitters: Bilal Jradeh, Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, UK and Kathleen Freson, Center for Molecular and Vascular Biology, Leuven, … (more) GoldVariant submitters: Bilal Jradeh, Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, UK and Kathleen Freson, Center for Molecular and Vascular Biology, Leuven, Belgium (less)	Publications: PubMed (1) PubMed: 34355501 Observation 1: Family history: no Observation 2: Clinical Features: hypodysfibrinogenemia (present)
Pathogenic (Oct 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial dysfibrinogenemia Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004175584.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023
Pathogenic (Jul 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004227445.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Comment: PP3, PP5, PM1, PM2, PM5, PS3, PS4_moderate Number of individuals with the variant: 4
Pathogenic (May 21, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Familial dysfibrinogenemia Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005185202.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Publications: PubMed (2) PubMed: 30349899‚ 29351094 Comment: Variant summary: FGG c.902G>A (p.Arg301His) results in a non-conservative amino acid change located in the Fibrinogen, alpha/beta/gamma chain, C-terminal globular domain (IPR002181) of the encoded … (more) Variant summary: FGG c.902G>A (p.Arg301His) results in a non-conservative amino acid change located in the Fibrinogen, alpha/beta/gamma chain, C-terminal globular domain (IPR002181) 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 8e-06 in 250136 control chromosomes. c.902G>A has been reported in the literature in multiple individuals affected with Dysfibrinogenemia (examples: Smith_2018 and Wang_2018). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.901C>T, p.Arg301Cys), supporting the critical relevance of codon 301 to FGG protein function. The following publications have been ascertained in the context of this evaluation (PMID: 30349899, 29351094). ClinVar contains an entry for this variant (Variation ID: 16362). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
other (Sep 19, 2014)	no assertion criteria provided Method: literature only	FIBRINOGEN HAIFA 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038056.2 First in ClinVar: Apr 04, 2013 Last updated: Sep 22, 2014	Publications: PubMed (5) PubMed: 3563970‚ 6654188‚ 2512677‚ 2976995‚ 1733971 Comment on evidence: Fibrinogen Haifa-1 has also been called fibrinogen Bergamo-2, Essen-1, Osaka-3, Perugia-1, and Saga-1. Reber et al. (1986) described the same substitution, namely, arginine-to-histidine at gamma-275 … (more) Fibrinogen Haifa-1 has also been called fibrinogen Bergamo-2, Essen-1, Osaka-3, Perugia-1, and Saga-1. Reber et al. (1986) described the same substitution, namely, arginine-to-histidine at gamma-275 (R275H), in the abnormal fibrinogen from 3 unrelated persons. In 1 family, there was a thrombotic tendency (616004). The substitution appears to be the same as that in fibrinogen Haifa (Brook et al., 1983), which was found in a patient with peripheral arterial thrombosis. See Siebenlist et al. (1989) and Yamazumi et al. (1988). Yoshida et al. (1992) demonstrated that fibrinogen Osaka III has the same mutational change. (less)

Comment:

Published functional studies suggest a damaging effect (PMID: 20508898); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.R275H; This variant is associated with the following publications: (PMID: 23683413, 30512152, 36964972, 34455742, 35063457, 7654933, 19132250, 3563970, 1455400, 2958955, 17604827, 30349899, 20546853, 30856382, 34355501, 29351094, 32877852, 20508898, 31064749)

Comment:

Variant summary: FGG c.902G>A (p.Arg301His) results in a non-conservative amino acid change located in the Fibrinogen, alpha/beta/gamma chain, C-terminal globular domain (IPR002181) 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 8e-06 in 250136 control chromosomes. c.902G>A has been reported in the literature in multiple individuals affected with Dysfibrinogenemia (examples: Smith_2018 and Wang_2018). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.901C>T, p.Arg301Cys), supporting the critical relevance of codon 301 to FGG protein function. The following publications have been ascertained in the context of this evaluation (PMID: 30349899, 29351094). ClinVar contains an entry for this variant (Variation ID: 16362). Based on the evidence outlined above, the variant was classified 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
GoldVariants, a resource for sharing rare genetic variants detected in bleeding, thrombotic, and platelet disorders: Communication from the ISTH SSC Subcommittee on Genomics in Thrombosis and Hemostasis.	Megy K	Journal of thrombosis and haemostasis : JTH	2021	PMID: 34355501
Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.	Downes K	Blood	2019	PMID: 31064749
Identification and characterization of novel mutations implicated in congenital fibrinogen disorders.	Smith N	Research and practice in thrombosis and haemostasis	2018	PMID: 30349899
Clinical and molecular characterization of nine Chinese patients affected by hypofibrinogenemia or dysfibrinogenemia.	Wang Y	Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis	2018	PMID: 29351094
Characterization of an abnormal fibrinogen Osaka V with the replacement of gamma-arginine 375 by glycine. The lack of high affinity calcium binding to D-domains and the lack of protective effect of calcium on fibrinolysis.	Yoshida N	The Journal of biological chemistry	1992	PMID: 1733971
The polymerization of fibrin prepared from fibrinogen Haifa (gamma 275Arg----His).	Siebenlist KR	Thrombosis and haemostasis	1989	PMID: 2512677
Normal plasmic cleavage of the gamma-chain variant of "fibrinogen Saga" with an Arg-275 to His substitution.	Yamazumi K	Thrombosis and haemostasis	1988	PMID: 2976995
Three abnormal fibrinogen variants with the same amino acid substitution (gamma 275 Arg----His): fibrinogens Bergamo II, Essen and Perugia.	Reber P	Thrombosis and haemostasis	1986	PMID: 3563970
Fibrinogen "Haifa" - a new fibrinogen variant. A case report.	Brook JG	Haemostasis	1983	PMID: 6654188

Text-mined citations for rs121913088 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_021870.2(FGG):c.902G>A (p.Arg301His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121913088 ...