rs1057519480

Variant names:

• chr6-1611162-CCT-C
• rs1057519480
• NM_001453.3:c.718_719delCT

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001453.3(FOXC1):​c.718_719delCT​(p.Leu240ValfsTer65) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L240L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FOXC1 NM_001453.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.534

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 14 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. Fraction of 0.568 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-1611162-CCT-C is Pathogenic according to our data. Variant chr6-1611162-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 375429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-1611162-CCT-C is described in Lovd as [Likely_pathogenic]. Variant chr6-1611162-CCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXC1	NM_001453.3	c.718_719delCT	p.Leu240ValfsTer65	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.718_719delCT	p.Leu240ValfsTer65	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

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Axenfeld-Rieger syndrome type 3 Pathogenic:3

Jun 23, 2022

Human Developmental Genetics Laboratory, Medical College of Wisconsin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 25, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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). 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. For these reasons, this variant has been classified as Pathogenic. -

Jun 11, 2015

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: no assertion criteria provided

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. -

Anterior segment dysgenesis 3 Pathogenic:1

Dec 21, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519480; hg19: chr6-1611397;