rs1057519479

Variant names:

• chr6-1611109-CGCATCCAGGACATCAA-C
• rs1057519479
• NM_001453.3:c.666_681delCATCCAGGACATCAAG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001453.3(FOXC1):​c.666_681delCATCCAGGACATCAAG​(p.Ile223ProfsTer87) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FOXC1 NM_001453.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.92

Genes affected

FOXC1 (HGNC:3800): (forkhead box C1) This gene belongs to the forkhead family of transcription factors which is characterized by a distinct DNA-binding forkhead domain. The specific function of this gene has not yet been determined; however, it has been shown to play a role in the regulation of embryonic and ocular development. Mutations in this gene cause various glaucoma phenotypes including primary congenital glaucoma, autosomal dominant iridogoniodysgenesis anomaly, and Axenfeld-Rieger anomaly. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 29 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-1611109-CGCATCCAGGACATCAA-C is Pathogenic according to our data. Variant chr6-1611109-CGCATCCAGGACATCAA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXC1	NM_001453.3	c.666_681delCATCCAGGACATCAAG	p.Ile223ProfsTer87	frameshift_variant	Exon 1 of 1	ENST00000645831.2	NP_001444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXC1	ENST00000645831.2	c.666_681delCATCCAGGACATCAAG	p.Ile223ProfsTer87	frameshift_variant	Exon 1 of 1		NM_001453.3	ENSP00000493906.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertelorism and tetralogy of fallot Pathogenic:1

Nov 16, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Ile223ProfsTer87 variant in FOXC1 was identified by our study in 2 family members with Axenfeld-Rieger syndrome, type 3. The variant has been reported in 2 related individuals with Axenfeld-Rieger syndrome, type 3 (PMID: 28513611) and was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 375428) as pathogenic by Molecular Pathology, SA Pathology. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 223 and leads to a premature termination codon 87 amino acids downstream. This gene is a single exon gene and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. While there is some evidence to suggest that heterozygous loss of function of the FOXC1 gene is a disease mechanism in Axenfeld-Rieger syndrome, type 3, this association is not yet strongly established based on the criteria laid out in Tayoun, 2018 (PMID: 30192042). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant Axenfeld-Rieger syndrome, type 3. ACMG/AMP Criteria applied: PM2, PVS1_moderate, PS4_supporting, PP1 (Richards 2015). -

Axenfeld-Rieger syndrome type 3 Pathogenic:1

May 16, 2016

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=9/191	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057519479; hg19: chr6-1611344;