VCV000016415.10 - ClinVar

NM_021871.4(FGA):c.510+1G>T

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_021871.4(FGA):c.510+1G>T

Variation ID: 16415 Accession: VCV000016415.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q31.3 4: 154587511 (GRCh38) [ NCBI UCSC ] 4: 155508663 (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	Oct 10, 2016	Dec 28, 2024	Sep 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_021871.4:c.510+1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_000508.5:c.510+1G>T		splice donor
NC_000004.12:g.154587511C>A
NC_000004.11:g.155508663C>A
NG_008832.1:g.8235G>T
LRG_557:g.8235G>T
LRG_557t1:c.510+1G>T

... more HGVS ... less HGVS

Protein change

Other names

p.?
IVS4DS, G-T, +1

Canonical SPDI

NC_000004.12:154587510:C: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.

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD) 0.00009

The Genome Aggregation Database (gnomAD), exomes 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00006

Links

ClinGen: CA126508 OMIM: 134820.0020 OMIM: 134820.0025 dbSNP: rs146387238 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.
FGA		-	-	GRCh38 GRCh37	247	279

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.
Congenital afibrinogenemia	Pathogenic (1)	no assertion criteria provided	Jul 1, 2000	RCV000017877.28
Familial hypodysfibrinogenemia	Pathogenic (1)	no assertion criteria provided	Apr 1, 2004	RCV000030942.28
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 19, 2024	RCV002513088.4
Hypofibrinogenemia	Pathogenic (1)	criteria provided, single submitter	Feb 1, 2019	RCV000851811.1
Congenital afibrinogenemia Familial dysfibrinogenemia Familial visceral amyloidosis, Ostertag type	Pathogenic (1)	criteria provided, single submitter	Mar 5, 2022	RCV002496394.1
Familial dysfibrinogenemia	Pathogenic (1)	criteria provided, single submitter	Jul 29, 2024	RCV004700245.1

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.
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: SCV000899779.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019	Publications: PubMed (1) PubMed: 31064749 Zygosity: Compound Heterozygote Sex: male Ethnicity/Population group: European
Pathogenic (Mar 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial visceral amyloidosis, Ostertag type Congenital afibrinogenemia Familial dysfibrinogenemia Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002811072.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Jul 25, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003289462.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 17576681‚ 9536098‚ 10891444‚ 30349899 Comment: This variant is present in population databases (rs146387238, gnomAD 0.009%). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus … (more) This variant is present in population databases (rs146387238, gnomAD 0.009%). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 16415). This variant is also known as IVS4+1G>T. Disruption of this splice site has been observed in individuals with hereditary fibrinogen abnormalities (PMID: 10891444, 30349899). This sequence change affects a donor splice site in intron 4 of the FGA gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. (less)
Pathogenic (Jul 29, 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: SCV005202257.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Publications: PubMed (1) PubMed: 10891444 Comment: Variant summary: FGA c.510+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more) Variant summary: FGA c.510+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of FGA function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.6e-05 in 251372 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in FGA causing Dysfibrinogenemia, Congenital, allowing no conclusion about variant significance. c.510+1G>T has been reported in the literature in multiple individuals affected with Afibrinogenaemia (e.g. Neerman-Arbez_2000). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 10891444). ClinVar contains an entry for this variant (Variation ID: 16415). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Sep 15, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005325200.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Comment: Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; … (more) Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 34255402, 31064749, 30349899, 10891444) (less)
Pathogenic (Sep 19, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005439152.1 First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024	Publications: PubMed (15) PubMed: 10891444‚ 11238133‚ 11354637‚ 14615374‚ 16651864‚ 17179831‚ 20598104‚ 24533951‚ 26763372‚ 29636644‚ 30019658‚ 30349899‚ 34255402‚ 36950719‚ 38286442
Pathogenic (Jul 01, 2000)	no assertion criteria provided Method: literature only	AFIBRINOGENEMIA, CONGENITAL Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038156.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 10, 2016	Publications: PubMed (1) PubMed: 10891444 Comment on evidence: Neerman-Arbez et al. (2000) collected data on 13 unrelated patients with congenital afibrinogenemia (202400). A common recurrent mutation at the donor splice site of FGA … (more) Neerman-Arbez et al. (2000) collected data on 13 unrelated patients with congenital afibrinogenemia (202400). A common recurrent mutation at the donor splice site of FGA intron 4 (IVS4G-T+1) accounted for 14 of the 26 (54%) alleles. (less)
Pathogenic (Apr 01, 2004)	no assertion criteria provided Method: literature only	HYPODYSFIBRINOGENEMIA, CONGENITAL Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038160.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 10, 2016	Publications: PubMed (1) PubMed: 14615374 Comment on evidence: See 134820.0024 and Lefebvre et al. (2004).

Comment:

This variant is present in population databases (rs146387238, gnomAD 0.009%). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 16415). This variant is also known as IVS4+1G>T. Disruption of this splice site has been observed in individuals with hereditary fibrinogen abnormalities (PMID: 10891444, 30349899). This sequence change affects a donor splice site in intron 4 of the FGA gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.

Comment:

Variant summary: FGA c.510+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of FGA function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.6e-05 in 251372 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in FGA causing Dysfibrinogenemia, Congenital, allowing no conclusion about variant significance. c.510+1G>T has been reported in the literature in multiple individuals affected with Afibrinogenaemia (e.g. Neerman-Arbez_2000). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 10891444). ClinVar contains an entry for this variant (Variation ID: 16415). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 34255402, 31064749, 30349899, 10891444)

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
Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the Prospective Rare Bleeding Disorders Database.	Mohsenian S	Blood advances	2024	PMID: 38286442
A Case Report of Congenital Afibrinogenemia and Literature Review of Management of Post-circumcision Bleeding.	Khan I	Cureus	2023	PMID: 36950719
Afibrinogenemia with two compound heterozygous mutations in FGA gene.	Feugray G	Haemophilia : the official journal of the World Federation of Hemophilia	2021	PMID: 34255402
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
Ischemic Strokes in a Man with Congenital Afibrinogenemia.	Nathoo N	The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques	2018	PMID: 30019658
Combined life-threatening thromboses and hemorrhages in a patient with afibrinogenemia and antithrombin deficiency.	Le Quellec S	Thrombosis journal	2018	PMID: 29636644
Recurrent VTE in a heterozygote of the fibrinogen Aα IVS4+1G>T and Aα p.Arg168Ter mutation.	Berens C	Thrombosis and haemostasis	2016	PMID: 26763372
Bone cysts in patients with afibrinogenaemia: a literature review and two new cases.	van Meegeren ME	Haemophilia : the official journal of the World Federation of Hemophilia	2014	PMID: 24533951
Is primary prophylaxis required in afibrinogenemia?	Polack B	Transfusion	2010	PMID: 20598104
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
A case of afibrinogenemia associated with A-alpha chain gene compound heterozygosity (HUMFIBRA c.[4110delA]+[3200+1G>T]).	Angles-Cano E	Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis	2007	PMID: 17179831
Inherited abnormalities of fibrinogen: 10-year clinical experience of an Italian group.	Santacroce R	Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis	2006	PMID: 16651864
Severe hypodysfibrinogenemia in compound heterozygotes of the fibrinogen AalphaIVS4 + 1G>T mutation and an AalphaGln328 truncation (fibrinogen Keokuk).	Lefebvre P	Blood	2004	PMID: 14615374
Molecular analysis of the fibrinogen gene cluster in 16 patients with congenital afibrinogenemia: novel truncating mutations in the FGA and FGG genes.	Neerman-Arbez M	Human genetics	2001	PMID: 11354637
Activation of multiple cryptic donor splice sites by the common congenital afibrinogenemia mutation, FGA IVS4 + 1 G-->T.	Attanasio C	Blood	2001	PMID: 11238133
Mutations in the fibrinogen aalpha gene account for the majority of cases of congenital afibrinogenemia.	Neerman-Arbez M	Blood	2000	PMID: 10891444
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098
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Text-mined citations for rs146387238 ...

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 Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_021871.4(FGA):c.510+1G>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs146387238 ...