rs1057519479

Positions:

• chr6-1611109-CGCATCCAGGACATCAA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001453.3(FOXC1):​c.666_681del​(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

Verdict is Pathogenic. Variant got 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/exons	MANE	UniProt
FOXC1	NM_001453.3	c.666_681del	p.Ile223ProfsTer87	frameshift_variant	1/1	ENST00000645831.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXC1	ENST00000645831.2	c.666_681del	p.Ile223ProfsTer87	frameshift_variant	1/1		NM_001453.3	P1

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

Likely pathogenic, criteria provided, single submitter

curation

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

Nov 16, 2020

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

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

May 16, 2016

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

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;