ClinVar Genomic variation as it relates to human health
NM_001453.3(FOXC1):c.718_719del (p.Leu240fs)
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
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NM_001453.3(FOXC1):c.718_719del (p.Leu240fs)
Variation ID: 375429 Accession: VCV000375429.24
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 6p25.3 6: 1611163-1611164 (GRCh38) [ NCBI UCSC ] 6: 1611398-1611399 (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 Feb 5, 2017 Jul 23, 2024 Dec 21, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001453.3:c.718_719del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001444.2:p.Leu240fs frameshift NM_001453.3:c.718_719delCT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001453.2:c.718_719delCT NC_000006.12:g.1611163_1611164del NC_000006.11:g.1611398_1611399del NG_009368.1:g.5718_5719del LRG_1245:g.5718_5719del LRG_1245t1:c.718_719del LRG_1245p1:p.Leu240fs - Protein change
- L240fs
- Other names
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- Canonical SPDI
- NC_000006.12:1611162:CT:
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
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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
Help
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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FOXC1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
533 | 674 |
Conditions - Germline
Condition
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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
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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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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 23, 2022 | RCV000416550.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 21, 2023 | RCV004594054.1 |
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
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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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Pathogenic
(Jun 23, 2022)
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criteria provided, single submitter
Method: research
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Axenfeld-Rieger syndrome type 3
Affected status: yes
Allele origin:
germline
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Human Developmental Genetics Laboratory, Medical College of Wisconsin
Accession: SCV002538959.1
First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022 |
Number of individuals with the variant: 3
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Pathogenic
(May 25, 2017)
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criteria provided, single submitter
Method: clinical testing
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Axenfeld-Rieger syndrome type 3
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000647085.4
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. A different truncation downstream of this variant (c.816_817delinsG) has been determined to be pathogenic (PMID: … (more)
For these reasons, this variant has been classified as Pathogenic. A different truncation downstream of this variant (c.816_817delinsG) has been determined to be pathogenic (PMID: 20881294). This suggests that deletion of this region of the FOXC1 protein is causative of disease. This variant has been reported to be de novo in an individual affected with Axenfeld-Rieger syndrome with developmental glaucoma (PMID: 16638984). ClinVar contains an entry for this variant (Variation ID: 375429). While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change results in a premature translational stop signal in the FOXC1 gene (p.Leu240Valfs*65). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 314 amino acids of the FOXC1 protein. (less)
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Pathogenic
(Dec 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Anterior segment dysgenesis 3
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767748.2
First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with Axenfeld-Rieger syndrome, type 3 (MIM #602482), anterior segment dysgenesis 3 (MIM #601631), congenital glaucoma (PMID: 31836490) and juvenile open angle glaucoma (PMID: 31836490). While loss of function has been functionally proven for some missense variants, the evidence for truncating variants is currently limited (PMID: 19513095). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variants in FOXC1 have been reported to demonstrate interfamilial and intrafamilial expressivity (PMIDs: 19513095; 31836490). 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0701 - Other protein-truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are greater than four protein-truncating variants located downstream of this variant (ClinVar; Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in ClinVar and has been observed as de novo in an internal VCGS patient and in an unrelated individual in the literature with FOXC1-related features (ClinVar, PMID: 16638984). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jun 11, 2015)
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no assertion criteria provided
Method: clinical testing
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Axenfeld-Rieger syndrome type 3
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Genetics and Molecular Pathology, SA Pathology
Accession: SCV000494261.1
First in ClinVar: Feb 05, 2017 Last updated: Feb 05, 2017 |
Comment:
Frame-shift introducing premature terminating codon (PTC) effecting functional haploinufficiency; clinical significance consistent with FOXC1 PTC variants found upstream and down stream of this position - … (more)
Frame-shift introducing premature terminating codon (PTC) effecting functional haploinufficiency; clinical significance consistent with FOXC1 PTC variants found upstream and down stream of this position - each regarded as pathogenic in published literature. (less)
Number of individuals with the variant: 1
Family history: no
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Australia
Secondary finding: no
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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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Axenfeld-Rieger syndrome: more than meets the eye. | Reis LM | Journal of medical genetics | 2023 | PMID: 35882526 |
Childhood glaucoma genes and phenotypes: Focus on FOXC1 mutations causing anterior segment dysgenesis and hearing loss. | Gauthier AC | Experimental eye research | 2020 | PMID: 31836490 |
Prevalence of FOXC1 Variants in Individuals With a Suspected Diagnosis of Primary Congenital Glaucoma. | Siggs OM | JAMA ophthalmology | 2019 | PMID: 30653210 |
Expanding the spectrum of FOXC1 and PITX2 mutations and copy number changes in patients with anterior segment malformations. | D'haene B | Investigative ophthalmology & visual science | 2011 | PMID: 20881294 |
Axenfeld-Rieger syndrome and spectrum of PITX2 and FOXC1 mutations. | Tümer Z | European journal of human genetics : EJHG | 2009 | PMID: 19513095 |
Structural assessment of PITX2, FOXC1, CYP1B1, and GJA1 genes in patients with Axenfeld-Rieger syndrome with developmental glaucoma. | Cella W | Investigative ophthalmology & visual science | 2006 | PMID: 16638984 |
Text-mined citations for rs1057519480 ...
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.