rs1057519475

Positions:

• chr6-1610761-C-T

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.316C>T​(p.Gln106Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FOXC1 NM_001453.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.33

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 88 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-1610761-C-T is Pathogenic according to our data. Variant chr6-1610761-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 375424.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.316C>T	p.Gln106Ter	stop_gained	1/1	ENST00000645831.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXC1	ENST00000645831.2	c.316C>T	p.Gln106Ter	stop_gained	1/1		NM_001453.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Axenfeld-Rieger syndrome type 3 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 09, 2018	For these reasons, this variant has been classified as Pathogenic. Different truncations (p.Gln120*, Leu240Valfs*65, p.Ser320Argfs*81) that lie downstream of this variant have been determined to be pathogenic (PMID: 20881294, 16638984, 18498376, 11782474). This suggests that deletion of this region of the FOXC1 protein is causative of disease. Experimental studies have shown that this nonsense change results in decreased protein half-life and increased transactivation (PMID: 25786029). This variant has been observed to segregate with Axenfeld-Rieger syndrome in a family (PMID: 28513611) and has also been observed in individuals affected with Axenfeld-Rieger syndrome (PMID: 20881294) or with bilateral primary congenital glaucoma (PMID: 25786029). ClinVar contains an entry for this variant (Variation ID: 375424). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the FOXC1 gene (p.Gln106*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 448 amino acids (~80%) of the FOXC1 protein. -
Pathogenic, no assertion criteria provided	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 19, 2014	Non-sense codon introduces 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 12, 2021

Published functional studies demonstrate a a hypermorphic effect of the Q106X variant, along with decreased protein stability and protein mis-localization; Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 448 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32224865, 20881294, 25786029, 30514661, 28513611, 28432732) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	D
Vest4		0.85
GERP RS		3.9

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: rs1057519475; hg19: chr6-1610996;