ClinVar Genomic variation as it relates to human health
NM_021870.3(FGG):c.124G>A (p.Gly42Ser)
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.
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(5); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_021870.3(FGG):c.124G>A (p.Gly42Ser)
Variation ID: 900593 Accession: VCV000900593.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q32.1 4: 154612201 (GRCh38) [ NCBI UCSC ] 4: 155533353 (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 May 31, 2020 May 12, 2024 Nov 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_021870.3:c.124G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_068656.2:p.Gly42Ser missense NM_000509.6:c.124G>A NP_000500.2:p.Gly42Ser missense NC_000004.12:g.154612201C>T NC_000004.11:g.155533353C>T NG_008834.1:g.5550G>A LRG_585:g.5550G>A LRG_585t1:c.124G>A LRG_585p1:p.Gly42Ser LRG_585t2:c.124G>A LRG_585p2:p.Gly42Ser - Protein change
- G42S
- Other names
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- Canonical SPDI
- NC_000004.12:154612200: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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0.00020 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
The Genome Aggregation Database (gnomAD) 0.00034
Exome Aggregation Consortium (ExAC) 0.00042
Trans-Omics for Precision Medicine (TOPMed) 0.00047
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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FGG | - | - |
GRCh38 GRCh37 |
135 | 169 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (1) |
criteria provided, single submitter
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Jan 12, 2018 | RCV001145946.5 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jul 7, 2023 | RCV001171744.24 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 15, 2023 | RCV002249738.3 |
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
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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
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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
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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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Uncertain significance
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Congenital afibrinogenemia
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001306655.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002517085.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Uncertain significance
(Nov 11, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001986327.2
First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023 |
Comment:
Reported using alternate nomenclature G16S in the heterozygous state in a female with dysfibrinogenemia, however, segregation information was not included (Pietrys et al., 2011; Wypasek … (more)
Reported using alternate nomenclature G16S in the heterozygous state in a female with dysfibrinogenemia, however, segregation information was not included (Pietrys et al., 2011; Wypasek et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28492530, 21725578, 27884173, 31479941, 27677677) (less)
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Uncertain significance
(Nov 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004222703.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: FGG c.124G>A (p.Gly42Ser) results in a non-conservative amino acid change located in the alpha/beta/gamma chain, coiled coil domain (IPR012290) of the encoded protein … (more)
Variant summary: FGG c.124G>A (p.Gly42Ser) results in a non-conservative amino acid change located in the alpha/beta/gamma chain, coiled coil domain (IPR012290) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. In addition, this variant disrupts the first nucleotide of exon 3, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00042 in 242562 control chromosomes in the gnomAD database, including 2 homozygotes. However, the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.124G>A has been reported in the literature in at least one heterozygous individual affected with symptomatic dysfibrinogenemia (e.g., Pietrys_2011, Wypasek_2019). This report does not provide unequivocal conclusions about association of the variant with Congenital Dysfibrinogenemia. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (e.g., Pietrys_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21725578, 31479941). Five submitters have reported this variant to ClinVar after 2014 with conflicting assessments (VUS, n = 4; likely benign, n = 1). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Jul 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003245324.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 42 of the FGG protein (p.Gly42Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 42 of the FGG protein (p.Gly42Ser). This variant is present in population databases (rs202132393, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of FGG-related conditions (PMID: 21725578). ClinVar contains an entry for this variant (Variation ID: 900593). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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)
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Likely benign
(Feb 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001334582.20
First in ClinVar: Jun 08, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552642.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The FGG p.Gly42Ser variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in … (more)
The FGG p.Gly42Ser variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs202132393) and in control databases in 109 of 273944 chromosomes (2 homozygous) at a frequency of 0.000398, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 10 of 7022 chromosomes (freq: 0.001424), Ashkenazi Jewish in 14 of 10212 chromosomes (freq: 0.001371), Latino in 26 of 34600 chromosomes (freq: 0.000751), European (non-Finnish) in 57 of 123364 chromosomes (freq: 0.000462) and African in 2 of 24438 chromosomes (freq: 0.000082), while the variant was not observed in the East Asian, European (Finnish) and South Asian populations. The p.Gly42 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.Gly42 variant occurs in the first base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, RNA analysis has not been performed to confirm this prediction. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Genetic and clinical characterization of congenital fibrinogen disorders in Polish patients: Identification of three novel fibrinogen gamma chain mutations. | Wypasek E | Thrombosis research | 2019 | PMID: 31479941 |
Two different fibrinogen gene mutations associated with bleeding in the same family (A αGly13Glu and γGly16Ser) and their impact on fibrin clot properties: fibrinogen Krakow II and Krakow III. | Pietrys D | Thrombosis and haemostasis | 2011 | PMID: 21725578 |
Text-mined citations for rs202132393 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.