ClinVar Genomic variation as it relates to human health
NM_023067.4(FOXL2):c.804dup (p.Gly269fs)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_023067.4(FOXL2):c.804dup (p.Gly269fs)
Variation ID: 4858 Accession: VCV000004858.8
- Type and length
-
Duplication, 1 bp
- Location
-
Cytogenetic: 3q22.3 3: 138945918-138945919 (GRCh38) [ NCBI UCSC ] 3: 138664760-138664761 (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 Apr 4, 2013 Aug 11, 2024 Mar 26, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_023067.4:c.804dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_075555.1:p.Gly269fs frameshift NC_000003.12:g.138945924dup NC_000003.11:g.138664766dup NG_012454.1:g.6222dup NG_029796.1:g.3691dup LRG_1295:g.6222dup LRG_1295t1:c.804dup LRG_1295p1:p.Gly269fs - Protein change
- G269fs
- Other names
- -
- Canonical SPDI
- NC_000003.12:138945918:GGGGGG:GGGGGGG
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
- Comment on variant
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 | ||
---|---|---|---|---|---|---|
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. |
|||
FOXL2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
236 | 271 |
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. |
---|---|---|---|---|
Pathogenic (1) |
no assertion criteria provided
|
Feb 1, 2003 | RCV000005132.2 | |
Pathogenic (1) |
no assertion criteria provided
|
Feb 1, 2003 | RCV000005133.2 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 1, 2017 | RCV000192036.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 26, 2023 | RCV000727228.6 | |
Pathogenic (1) |
criteria provided, single submitter
|
Mar 26, 2024 | RCV004619186.1 |
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
(Jul 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004293514.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gly269Argfs*265) in the FOXL2 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Gly269Argfs*265) in the FOXL2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 108 amino acid(s) of the FOXL2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with blepharophimosis (PMID: 17277738). ClinVar contains an entry for this variant (Variation ID: 4858). This variant disrupts a region of the FOXL2 protein in which other variant(s) (p.Ala304Hisfs*52) have been determined to be pathogenic (PMID: 11468277). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Nov 03, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Blepharophimosis, ptosis, and epicanthus inversus syndrome
Affected status: yes
Allele origin:
germline
|
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000484892.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
Comment:
Clinical Testing
|
Number of individuals with the variant: 3
|
|
Pathogenic
(Mar 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000706764.2
First in ClinVar: Oct 05, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
Pathogenic
(Jan 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Blepharophimosis, ptosis, and epicanthus inversus syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo,
paternal,
unknown
|
Wessex Regional Genetics Laboratory, Salisbury District Hospital
Accession: SCV000924437.1
First in ClinVar: Jun 23, 2019 Last updated: Jun 23, 2019 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Observation 3:
Number of individuals with the variant: 1
Observation 4:
Number of individuals with the variant: 1
|
|
Pathogenic
(Mar 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV005118627.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
The c.804dupC (p.G269Rfs*265) alteration, located in exon 1 (coding exon 1) of the FOXL2 gene, consists of a duplication of C at position 804, causing … (more)
The c.804dupC (p.G269Rfs*265) alteration, located in exon 1 (coding exon 1) of the FOXL2 gene, consists of a duplication of C at position 804, causing a translational frameshift with a predicted alternate stop codon after 265 amino acids. Frameshifts are typically deleterious in nature; however, because FOXL2 is a single-exon gene this alteration is not expected to trigger nonsense-mediated mRNA decay and an altered protein could still be expressed. This frameshift impacts the last 29% of the native protein and results in the elongation of the protein by 157 amino acids. The exact functional impact of these altered amino acids is unknown at this time. The FOXL2 c.804dupC alteration was flagged as a low confidence call in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES), some of which also had a family history of BPES, and this variant was shown to segregate with disease in one family (Wang, 2007; Kaur, 2011; Bunyan, 2019). Additionally, this variant was detected de novo in one female with premature ovarian insufficiency, narrow palpebral fissures, and polycystic ovary morphology (Shen, 2021). Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
Pathogenic
(Feb 01, 2003)
|
no assertion criteria provided
Method: literature only
|
BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000025309.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 2 families with BPES II (110100), De Baere et al. (2001) found that affected members had a 1-bp cytosine insertion following position 1041, resulting … (more)
In 2 families with BPES II (110100), De Baere et al. (2001) found that affected members had a 1-bp cytosine insertion following position 1041, resulting in 264 novel amino acids beginning at codon 268 and extending the protein from 376 amino acids to 532 amino acids. De Baere et al. (2003) found this mutation in a family with BPES I. They stated that this was the first mutation shown to lead to both BPES types in different families (interfamilial phenotypic variability). (less)
|
|
Pathogenic
(Feb 01, 2003)
|
no assertion criteria provided
Method: literature only
|
BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000025310.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 2 families with BPES II (110100), De Baere et al. (2001) found that affected members had a 1-bp cytosine insertion following position 1041, resulting … (more)
In 2 families with BPES II (110100), De Baere et al. (2001) found that affected members had a 1-bp cytosine insertion following position 1041, resulting in 264 novel amino acids beginning at codon 268 and extending the protein from 376 amino acids to 532 amino acids. De Baere et al. (2003) found this mutation in a family with BPES I. They stated that this was the first mutation shown to lead to both BPES types in different families (interfamilial phenotypic variability). (less)
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Blepharophimosis, ptosis, and epicanthus inversus syndrome
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000207362.2
First in ClinVar: Oct 05, 2015 Last updated: Oct 01, 2022 |
|
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 |
---|---|---|---|---|
Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome. | Adam MP | - | 2022 | PMID: 20301614 |
Genetic etiologic analysis in 74 Chinese Han women with idiopathic premature ovarian insufficiency by combined molecular genetic testing. | Shen J | Journal of assisted reproduction and genetics | 2021 | PMID: 33538981 |
Screening of a large cohort of blepharophimosis, ptosis, and epicanthus inversus syndrome patients reveals a very strong paternal inheritance bias and a wide spectrum of novel FOXL2 mutations. | Bunyan DJ | European journal of medical genetics | 2019 | PMID: 31077882 |
Mutation spectrum of fork-head transcriptional factor gene (FOXL2) in Indian Blepharophimosis Ptosis Epicanthus Inversus Syndrome (BPES) patients. | Kaur I | The British journal of ophthalmology | 2011 | PMID: 21325395 |
FOXL2 mutations in Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome. | Wang J | Molecular vision | 2007 | PMID: 17277738 |
FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation. | De Baere E | American journal of human genetics | 2003 | PMID: 12529855 |
Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype--phenotype correlation. | De Baere E | Human molecular genetics | 2001 | PMID: 11468277 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FOXL2 | - | - | - | - |
Text-mined citations for rs797044528 ...
HelpRecord last updated Sep 29, 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.
NCBI staff reviewed the sequence information reported in PubMed 1468277 Fig. 2Q to determine the location of this allele on the current reference sequence.