rs1057519478

Variant names:

• chr6-1611037-GGCCGCCAGCCCCCGCCCGC-G
• rs1057519478
• NM_001453.3:c.599_617delAGCCCCCGCCCGCGCCGCC

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.599_617delAGCCCCCGCCCGCGCCGCC​(p.Gln200ArgfsTer109) 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 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:3
• Conservation: PhyloP100: 2.14

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 0.64 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 6-1611037-GGCCGCCAGCCCCCGCCCGC-G is Pathogenic according to our data. Variant chr6-1611037-GGCCGCCAGCCCCCGCCCGC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375427.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.599_617delAGCCCCCGCCCGCGCCGCC	p.Gln200ArgfsTer109	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.599_617delAGCCCCCGCCCGCGCCGCC	p.Gln200ArgfsTer109	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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Axenfeld-Rieger syndrome type 3 Pathogenic:2

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. -

Jul 20, 2018

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FOXC1 is a single exon gene and therefore the consequence of this frameshifting mutation is difficult to predict. However, loss-of-function variants upstream and downstream of the c.599_617del (p.Gln200ArgfsTer109) have been reported in individuals with Axenfeld-Rieger syndrome (PMID: 28513611), supporting the putative pathogenicity of this variant. Additionally, c.599_617del (p.Gln200ArgfsTer109) variant in FOXC1 has been reported as a heterozygous change in an individual with early-onset glaucoma and additional ophthalmologic anomalies including posterior embryotoxin, peripheral anterior synechiae, corneal edema, and ectropion uveae (PMID: 28513611). This variant is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Based on the available evidence, the c.599_617del (p.Gln200ArgfsTer109) variant is classified as pathogenic. -

not provided Pathogenic:1

Nov 06, 2020

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 354 amino acids are lost and replaced with 108 incorrect amino acids; Not observed in large population cohorts (Lek et al., 2016); Previously reported in a 26 year old female with peripheral anterior synechiae (PAS), corneal edema, ectropion uveae and glaucoma, and no other systemic symptoms (Souzeau et al., 2017); This variant is associated with the following publications: (PMID: 28513611) -

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: rs1057519478; hg19: chr6-1611272;