ClinVar Genomic variation as it relates to human health
NM_005251.3(FOXC2):c.361C>T (p.Arg121Cys)
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_005251.3(FOXC2):c.361C>T (p.Arg121Cys)
Variation ID: 599242 Accession: VCV000599242.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q24.1 16: 86567696 (GRCh38) [ NCBI UCSC ] 16: 86601302 (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 Jan 7, 2019 May 1, 2024 May 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005251.3:c.361C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005242.1:p.Arg121Cys missense NR_125795.1:n.66G>A non-coding transcript variant NC_000016.10:g.86567696C>T NC_000016.9:g.86601302C>T NG_012025.2:g.5868C>T LRG_1292:g.5868C>T LRG_1292t1:c.361C>T LRG_1292p1:p.Arg121Cys - Protein change
- R121C
- Other names
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- Canonical SPDI
- NC_000016.10:86567695: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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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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FOXC2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
137 | 235 | |
FOXC2-AS1 | - | - | - | GRCh38 | - | 69 |
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
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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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Feb 22, 2023 | RCV000735835.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 18, 2020 | RCV001811460.13 | |
Pathogenic (1) |
criteria provided, single submitter
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May 26, 2023 | RCV003258957.9 |
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. |
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Pathogenic
(May 10, 2019)
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criteria provided, single submitter
Method: clinical testing
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Distichiasis-lymphedema syndrome
Affected status: yes
Allele origin:
de novo
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Center for Molecular Medicine, Children’s Hospital of Fudan University
Accession: SCV001190559.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
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Likely pathogenic
(Feb 18, 2020)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001477871.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The FOXC2 c.361C>T; p.Arg121Cys variant is reported in the literature in several individuals affected with primary lymphedema (Lyons 2017, Sargent 2014, van Steensel 2009). This … (more)
The FOXC2 c.361C>T; p.Arg121Cys variant is reported in the literature in several individuals affected with primary lymphedema (Lyons 2017, Sargent 2014, van Steensel 2009). This variant was found to segregate with disease in several members of a family with hereditary lymphedema (Sargent 2014). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 121 is highly conserved, and it occurs in the forkhead DNA-binding domain and interacts with bases in the DNA major groove (Li 2019). Functional assays show that the p.Arg121Cys variant lacks measurable transcriptional activation activity in cultured cells (van Steensel 2009). Additionally, another amino acid substitution at this codon (p.Arg121His) has been reported in an individual with hereditary lymphedema and lacks DNA-binding and transcriptional activation activity (Berry 2005). Based on available information, the p.Arg121Cys variant is considered to be likely pathogenic. References: Berry FB et al. The establishment of a predictive mutational model of the forkhead domain through the analyses of FOXC2 missense mutations identified in patients with hereditary lymphedema with distichiasis. Hum Mol Genet. 2005 Sep 15;14(18):2619-27. Li S et al. Crystal Structure of FOXC2 in Complex with DNA Target. ACS Omega. 2019 Jun 24;4(6):10906-10914. Lyons O et al. Human venous valve disease caused by mutations in FOXC2 and GJC2. J Exp Med. 2017 Jul 19. pii: jem.20160875. Sargent C et al. A five generation family with a novel mutation in FOXC2 and lymphedema worsening to hydrops in the youngest generation. Am J Med Genet A. 2014 Nov;164A(11):2802-7. van Steensel MA et al. Novel missense mutations in the FOXC2 gene alter transcriptional activity. Hum Mutat. 2009 Dec;30(12):E1002-9. (less)
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Pathogenic
(Feb 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Distichiasis-lymphedema syndrome
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV004014729.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The FOXC2 c.361C>T (p.Arg121Cys) missense variant results in the substitution of arginine at amino acid position 121 with cysteine. Across a selection of the available … (more)
The FOXC2 c.361C>T (p.Arg121Cys) missense variant results in the substitution of arginine at amino acid position 121 with cysteine. Across a selection of the available literature, the c.361C>T variant has been identified in at least five unrelated individuals, of whom two had acquired it de novo (PMID: 19760751; PMID: 25252123; PMID: 28724617; PMID: 32411386; PMID: 33897756). Functional studies demonstrated that the protein containing this variant shows altered transcriptional activity (PMID: 19760751). This variant is located in the forkhead domain and affects a residue that is important for DNA binding (PMID: 31460188). A different amino acid change at the same position, p.Arg121His, has been reported in the literature in an individual with lymphedema, and experimental evidence suggests damaging effect of this variant on the protein function (PMID: 12114478; PMID: 16081467; PMID: 27276711). The p.Arg121Cys variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.361C>T (p.Arg121Cys) variant is classified as pathogenic for lymphedema-distichiasis syndrome. (less)
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Pathogenic
(May 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003981486.2
First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024 |
Comment:
The c.361C>T (p.R121C) alteration is located in exon 1 (coding exon 1) of the FOXC2 gene. This alteration results from a C to T substitution … (more)
The c.361C>T (p.R121C) alteration is located in exon 1 (coding exon 1) of the FOXC2 gene. This alteration results from a C to T substitution at nucleotide position 361, causing the arginine (R) at amino acid position 121 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The c.361C<T alteration as been observed in multiple individuals with primary lymphedema (van Steensel, 2009; Sargent, 2014; Lyons, 2017) and as a recurrent de novo alteration in individuals with clinical features consistent with lymphedema-distichiasis syndrome (Wang, 2020; Zhou, 2021). This amino acid position is highly conserved in available vertebrate species. This alteration is located in the forkhead domain of the FOXC2 gene. Majority of reported disease-causing variants in the forkhead domain cause haploinsufficiency and reduce transactivation activity, while some variants outside of this region enhance transactivation activity (van Steensel, 2009; Jiang, 2022). Luciferase assays measuring FOXC2 transactivational activity have shown that the p.R121C alteration decreases transcriptional activity (van Steensel, 2009; Jiang, 2022). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Jan 02, 2019)
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no assertion criteria provided
Method: literature only
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LYMPHEDEMA-DISTICHIASIS SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000863987.1
First in ClinVar: Jan 07, 2019 Last updated: Jan 07, 2019 |
Comment on evidence:
From a cohort of 288 patients with primary noncongenital lymphedema, van Steensel et al. (2009) identified 1 patient with lymphedema-distichiasis syndrome (LPHDST; 153400) who was … (more)
From a cohort of 288 patients with primary noncongenital lymphedema, van Steensel et al. (2009) identified 1 patient with lymphedema-distichiasis syndrome (LPHDST; 153400) who was heterozygous for a c.361C-T transition (GenBank NG_012025.1) in the FOXC2 gene, resulting in an arg121-to-cys (R121C) substitution at a highly conserved residue within the forkhead domain. The mutation was not found in 100 Dutch controls or in the dbSNP (build 130) database. The patient had swelling of feet and neck at birth, developed lymphedema, and also had superficial and deep venous insufficiency. Although distichiasis was not reported, the authors noted that it is a feature that can be quite subtle and might have been missed. Functional analysis in HeLa Ohio and COS-7 cells showed reduced transcriptional and transactivation activity with the R121C mutant compared to wildtype FOXC2. (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 landscape of FOXC2 mutations in lymphedema-distichiasis syndrome: Different mechanism of pathogenicity for mutations in different domains. | Jiang L | Experimental eye research | 2022 | PMID: 35716761 |
Value of Exome Sequencing in Diagnosis and Management of Recurrent Non-immune Hydrops Fetalis: A Retrospective Analysis. | Zhou X | Frontiers in genetics | 2021 | PMID: 33897756 |
Clinical utility of 24-h rapid trio-exome sequencing for critically ill infants. | Wang H | NPJ genomic medicine | 2020 | PMID: 32411386 |
Crystal Structure of FOXC2 in Complex with DNA Target. | Li S | ACS omega | 2019 | PMID: 31460188 |
Human venous valve disease caused by mutations in FOXC2 and GJC2. | Lyons O | The Journal of experimental medicine | 2017 | PMID: 28724617 |
FOXC2 disease-mutations identified in lymphedema-distichiasis patients cause both loss and gain of protein function. | Tavian D | Oncotarget | 2016 | PMID: 27276711 |
A five generation family with a novel mutation in FOXC2 and lymphedema worsening to hydrops in the youngest generation. | Sargent C | American journal of medical genetics. Part A | 2014 | PMID: 25252123 |
Novel missense mutations in the FOXC2 gene alter transcriptional activity. | van Steensel MA | Human mutation | 2009 | PMID: 19760751 |
The establishment of a predictive mutational model of the forkhead domain through the analyses of FOXC2 missense mutations identified in patients with hereditary lymphedema with distichiasis. | Berry FB | Human molecular genetics | 2005 | PMID: 16081467 |
Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24. | Brice G | Journal of medical genetics | 2002 | PMID: 12114478 |
Text-mined citations for rs1567571184 ...
HelpRecord last updated May 01, 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.