VCV000016365.5 - ClinVar

NM_021870.2(FGG):c.1001A>T (p.Asn334Ile)

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.

(3)

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.

Uncertain significance

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.1001A>T (p.Asn334Ile)

Variation ID: 16365 Accession: VCV000016365.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q32.1 4: 154606833 (GRCh38) [ NCBI UCSC ] 4: 155527985 (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, 2014	Sep 29, 2024	Jan 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_021870.3:c.1001A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_068656.2:p.Asn334Ile	missense
NM_000509.4:c.1001A>T
NM_000509.6:c.1001A>T	NP_000500.2:p.Asn334Ile	missense
NC_000004.12:g.154606833T>A
NC_000004.11:g.155527985T>A
NG_008834.1:g.10918A>T
LRG_585:g.10918A>T
LRG_585t1:c.1001A>T	LRG_585p1:p.Asn334Ile
LRG_585t2:c.1001A>T	LRG_585p2:p.Asn334Ile
	P02679:p.Asn334Ile

... more HGVS ... less HGVS

Protein change

N334I

Other names

N308I

Canonical SPDI

NC_000004.12:154606832:T: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.

0.00020 (A)

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

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA126396 UniProtKB: P02679#VAR_002413 OMIM: 134850.0005 dbSNP: rs121913090 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.
FIBRINOGEN BALTIMORE 3	other (1)	no assertion criteria provided	Sep 26, 2014	RCV000017785.2
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 26, 2024	RCV002513087.3

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.
Uncertain significance (Sep 22, 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: SCV003491125.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 2328317‚ 3175983 Comment: This variant is present in population databases (rs121913090, gnomAD 0.02%). In summary, the available evidence is currently insufficient to determine the role of this variant … (more) This variant is present in population databases (rs121913090, gnomAD 0.02%). 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. 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) performed at Invitae indicates that this missense variant is expected to disrupt FGG protein function. ClinVar contains an entry for this variant (Variation ID: 16365). This variant is also known as Asn308Ile. This missense change has been observed in individual(s) with dysfibrinogenemia (PMID: 2328317, 3175983). This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 334 of the FGG protein (p.Asn334Ile). (less)
Uncertain significance (Jan 26, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005325104.1 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; Also known as Asn308Ile or Fibrinogen Baltimore III; This variant … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as Asn308Ile or Fibrinogen Baltimore III; This variant is associated with the following publications: (PMID: 2328317, 33260935, 3175983) (less)
other (Sep 26, 2014)	no assertion criteria provided Method: literature only	FIBRINOGEN BALTIMORE 3 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038064.2 First in ClinVar: Apr 04, 2013 Last updated: Sep 29, 2014	Publications: PubMed (2) PubMed: 3175983‚ 2328317 Comment on evidence: Ebert and Bell (1988) identified Baltimore-3 as a congenital abnormal fibrinogen with defective fibrin monomer polymerization. Bantia et al. (1990) demonstrated an asn308-to-ile mutation (N308I). … (more) Ebert and Bell (1988) identified Baltimore-3 as a congenital abnormal fibrinogen with defective fibrin monomer polymerization. Bantia et al. (1990) demonstrated an asn308-to-ile mutation (N308I). Polymerization is also affected by N308K (134850.0004). (less)

Comment:

This variant is present in population databases (rs121913090, gnomAD 0.02%). 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. 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) performed at Invitae indicates that this missense variant is expected to disrupt FGG protein function. ClinVar contains an entry for this variant (Variation ID: 16365). This variant is also known as Asn308Ile. This missense change has been observed in individual(s) with dysfibrinogenemia (PMID: 2328317, 3175983). This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 334 of the FGG protein (p.Asn334Ile).

Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as Asn308Ile or Fibrinogen Baltimore III; This variant is associated with the following publications: (PMID: 2328317, 33260935, 3175983)

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
Polymerization defect of fibrinogen Baltimore III due to a gamma Asn308----Ile mutation.	Bantia S	Blood	1990	PMID: 2328317
Fibrinogen Baltimore III: congenital dysfibrinogenemia with a shortened gamma-subunit.	Ebert RF	Thrombosis research	1988	PMID: 3175983

Text-mined citations for rs121913090 ...

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_021870.2(FGG):c.1001A>T (p.Asn334Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121913090 ...