VCV000626970.6 - ClinVar

NM_021870.3(FGG):c.1099G>A (p.Ala367Thr)

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.

(5)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(2); Uncertain significance(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_021870.3(FGG):c.1099G>A (p.Ala367Thr)

Variation ID: 626970 Accession: VCV000626970.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q32.1 4: 154606735 (GRCh38) [ NCBI UCSC ] 4: 155527887 (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 29, 2019	Sep 29, 2024	Dec 21, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_021870.3:c.1099G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_068656.2:p.Ala367Thr	missense
NM_000509.4:c.1099G>A
NM_000509.6:c.1099G>A	NP_000500.2:p.Ala367Thr	missense
NC_000004.12:g.154606735C>T
NC_000004.11:g.155527887C>T
NG_008834.1:g.11016G>A
LRG_585:g.11016G>A
LRG_585t1:c.1099G>A	LRG_585p1:p.Ala367Thr
LRG_585t2:c.1099G>A	LRG_585p2:p.Ala367Thr

... more HGVS ... less HGVS

Protein change

A367T

Other names

Canonical SPDI

NC_000004.12:154606734: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.

0.00060 (T)

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

The Genome Aggregation Database (gnomAD), exomes 0.00003

The Genome Aggregation Database (gnomAD) 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00004

Exome Aggregation Consortium (ExAC) 0.00007

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

1000 Genomes Project 0.00060

1000 Genomes Project 30x 0.00062

Links

dbSNP: rs78257946 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	144	178

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.
Hypofibrinogenemia	Likely pathogenic (1)	criteria provided, single submitter	Feb 1, 2019	RCV000851656.1
Familial dysfibrinogenemia	Likely pathogenic (1)	criteria provided, single submitter	-	RCV002222049.3
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Sep 24, 2023	RCV003558570.2
not specified	Uncertain significance (1)	criteria provided, single submitter	Dec 21, 2023	RCV003489859.1

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.
Likely 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: SCV000899424.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019	Publications: PubMed (1) PubMed: 31064749 Sex: male Ethnicity/Population group: European
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial dysfibrinogenemia Affected status: yes Allele origin: germline	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology Accession: SCV002499579.2 First in ClinVar: Apr 23, 2022 Last updated: Jul 22, 2023 Comment: Submitted to the GoldVariant database by Kathleen Freson, Center for Molecular and Vascular Biology	Clinical Features: Dysfibrinogenemia (present)
Uncertain significance (Dec 21, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004241583.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Publications: PubMed (4) PubMed: 31064749‚ 17849064‚ 35853369‚ 23061815 Comment: Variant summary: FGG c.1099G>A (p.Ala367Thr) 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.1099G>A (p.Ala367Thr) 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. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251306 control chromosomes (gnomAD). c.1099G>A has been reported in the literature in individuals affected with Congenital Dysfibrinogenemia/Hypofibrinogenemia (Hanss_2007, Shapiro_2013, Downes_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31064749, 35853369, 23061815, 17849064). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
Uncertain significance (Sep 06, 2023)	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: SCV004292759.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 17849064‚ 31064749 Comment: This missense change has been observed in individual(s) with clinical features of hypofibrinogenemia (PMID: 17849064, 31064749). This sequence change replaces alanine, which is neutral and … (more) This missense change has been observed in individual(s) with clinical features of hypofibrinogenemia (PMID: 17849064, 31064749). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 367 of the FGG protein (p.Ala367Thr). This variant is present in population databases (rs78257946, gnomAD 0.03%). This variant is also known as gammaAla341Thr and fibrinogen Lyon III. . ClinVar contains an entry for this variant (Variation ID: 626970). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGG protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Sep 24, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005325103.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in a patient with a suspected bleeding, thrombotic, or … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in a patient with a suspected bleeding, thrombotic, or platelet disorder; however, familial segregation information and additional clinical information were not included (PMID: 31064749); This variant is associated with the following publications: (PMID: 20981092, 17849064, 31064749) (less)

Comment:

Variant summary: FGG c.1099G>A (p.Ala367Thr) 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. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251306 control chromosomes (gnomAD). c.1099G>A has been reported in the literature in individuals affected with Congenital Dysfibrinogenemia/Hypofibrinogenemia (Hanss_2007, Shapiro_2013, Downes_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31064749, 35853369, 23061815, 17849064). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Comment:

This missense change has been observed in individual(s) with clinical features of hypofibrinogenemia (PMID: 17849064, 31064749). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 367 of the FGG protein (p.Ala367Thr). This variant is present in population databases (rs78257946, gnomAD 0.03%). This variant is also known as gammaAla341Thr and fibrinogen Lyon III. . ClinVar contains an entry for this variant (Variation ID: 626970). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGG protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in a patient with a suspected bleeding, thrombotic, or platelet disorder; however, familial segregation information and additional clinical information were not included (PMID: 31064749); This variant is associated with the following publications: (PMID: 20981092, 17849064, 31064749)

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 (hypo-)dysfibrinogenemia and bleeding: A systematic literature review.	Li Y	Thrombosis research	2022	PMID: 35853369
Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.	Downes K	Blood	2019	PMID: 31064749
Clinical phenotype, laboratory features and genotype of 35 patients with heritable dysfibrinogenaemia.	Shapiro SE	British journal of haematology	2013	PMID: 23061815
Clinical and biological features of 3 cases of hypofibrinogenemia associated with three different mutations (gamma Ala341Thr, Bbeta Tyr326Cys and Aalpha Asp496Asn).	Hanss M	Thrombosis and haemostasis	2007	PMID: 17849064

Text-mined citations for rs78257946 ...

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 08, 2024

ClinVar Genomic variation as it relates to human health

NM_021870.3(FGG):c.1099G>A (p.Ala367Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs78257946 ...