ClinVar Genomic variation as it relates to human health
NM_001377304.1(GFI1B):c.503G>T (p.Cys168Phe)
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.
Pathogenic(1); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001377304.1(GFI1B):c.503G>T (p.Cys168Phe)
Variation ID: 1695382 Accession: VCV001695382.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.13 9: 132988461 (GRCh38) [ NCBI UCSC ] 9: 135863848 (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 Jul 18, 2022 Oct 28, 2023 Aug 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001377304.1:c.503G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001364233.1:p.Cys168Phe missense NM_001135031.2:c.503G>T NP_001128503.1:p.Cys168Phe missense NM_001371908.1:c.503G>T NP_001358837.1:p.Cys168Phe missense NM_001377305.1:c.503G>T NP_001364234.1:p.Cys168Phe missense NM_004188.7:c.503G>T NM_004188.8:c.503G>T NP_004179.3:p.Cys168Phe missense NC_000009.12:g.132988461G>T NC_000009.11:g.135863848G>T NG_034227.1:g.47917G>T LRG_879:g.47917G>T - Protein change
- C168F
- Other names
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- Canonical SPDI
- NC_000009.12:132988460:G: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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0.00100 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00049
1000 Genomes Project 30x 0.00109
Exome Aggregation Consortium (ExAC) 0.00060
1000 Genomes Project 0.00100
- 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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GFI1B | - | - |
GRCh38 GRCh37 |
89 | 133 |
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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 29, 2020 | RCV002264884.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 15, 2023 | RCV003321917.2 |
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 29, 2020)
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criteria provided, single submitter
Method: clinical testing
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Platelet-type bleeding disorder 17
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761426.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Platelet-type bleeding disorder 17
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Lifecell International Pvt. Ltd
Accession: SCV003842252.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
A Heterozygous Missense variant c.503G>T in Exon 8 of the GFI1B gene that results in the amino acid substitution p.Cys168Phe was identified. The observed variant … (more)
A Heterozygous Missense variant c.503G>T in Exon 8 of the GFI1B gene that results in the amino acid substitution p.Cys168Phe was identified. The observed variant has a minor allele frequency of 0.00049% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Uncertain significance: Pathogenic (1); with a status of (1 star) criteria provided, single submitter (Variation ID 1695382 as of 2022-12-17). Mutations in the gene have been documented to cause Platelet-type bleeding disorder 17 (Monteferrario, Davide et al., 2014). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines. (less)
Ethnicity/Population group: Asian
Geographic origin: India
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Platelet-type bleeding disorder 17
Affected status: yes
Allele origin:
germline
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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002546500.2
First in ClinVar: Jul 18, 2022 Last updated: Jul 22, 2023
Comment:
Submitted to the GoldVariant database by Dr Marie-Christine Morel-Kopp; Northern Blood Research Centre, Sydney, Australia
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Clinical Features:
Bleeding (present)
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Likely pathogenic
(Aug 15, 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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004027558.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Platelet-type bleeding disorder 17
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047021.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The missense variant p.C168F in GFI1B (NM_004188.6) has been previously reported in individuals as homozygous as well as heterozygous forms (Cheng et al, 2019). However, … (more)
The missense variant p.C168F in GFI1B (NM_004188.6) has been previously reported in individuals as homozygous as well as heterozygous forms (Cheng et al, 2019). However, individuals with homozygous C168F variant suffered from clinical bleeding symptoms with thrombocytopenia and platelet aggregation dysfunction whereas heterozygous C168F patients only displayed macrothrombocytopenia with platelet CD34 expression (partial effect on the phenotype) (van Oorschot, Rinske et al, 2019). Experimental studies suggest that this mutation causes de-repression of other genes through disruption of the protein’s usual transcriptional repressor activity (Rabbolini et al, 2017). This variant has a gnomAD allele frequency of 0.04899 % and 5/978 (0.5112%) alleles from individuals of South Asian background in 1000 Genomes. It has been observed in homozygous form in two control individuals in the Gnomad database. The p.C168F missense variant is predicted to be damaging by both SIFT and PolyPhen2. The cysteine residue at codon 168 of GFI1B is conserved in all mammalian species. The nucleotide c.503 in GFI1B is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of thrombocytes (present)
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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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A dominant-negative GFI1B mutation in the gray platelet syndrome. | Monteferrario D | The New England journal of medicine | 2014 | PMID: 24325358 |
Text-mined citations for rs527297896 ...
HelpRecord last updated May 08, 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.