rs121909338

Variant names:

• chr6-1610833-C-T
• rs121909338
• NM_001453.3:c.388C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001453.3(FOXC1):​c.388C>T​(p.Leu130Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FOXC1 NM_001453.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 2.72
• Publications: 9 publications found

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]

FOXC1 Gene-Disease associations (from GenCC):

• anterior segment dysgenesis 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• Axenfeld-Rieger syndrome type 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• aniridia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Axenfeld anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Axenfeld-Rieger syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated aniridia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Peters anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Rieger anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001453.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Trascript score misZ: -3.6526 (below the threshold of 3.09). GenCC associations: The gene is linked to Rieger anomaly, Axenfeld-Rieger syndrome type 3, anterior segment dysgenesis 3, isolated aniridia, Axenfeld-Rieger syndrome, Axenfeld anomaly, aniridia, Peters anomaly.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 6-1610833-C-T is Pathogenic according to our data. Variant chr6-1610833-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8460.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXC1	NM_001453.3	c.388C>T	p.Leu130Phe	missense_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.388C>T	p.Leu130Phe	missense_variant	Exon 1 of 1		NM_001453.3	ENSP00000493906.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000148 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Axenfeld-Rieger syndrome type 3 Pathogenic:4

Jan 20, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 18, 2024

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Nov 28, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this is a rare missense change that disrupts protein function in cell culture and has been observed in affected individuals. In the absence of additional genetic data, this variant has been classified as Likely Pathogenic. Experimental evidence suggest this variant results in a severely impaired FOXC1 protein that forms aggregates in the cytoplasm, has reduced localization to the nucleus, reduced DNA binding and reduced transactivation ability (PMID: 19279310, 17013732, 17210863). In addition, expression of this variant in human trabecular meshwork cells shows reduced activity and increased cell death compared to expression of wild type FOXC1 protein (PMID: 24556684). This variant has been reported in individuals with Axenfled-Rieger syndrome (PMID: 17197537, 17210863) and it has been shown to arise de novo in one individual (PMID: 17210863). ClinVar contains an entry for this variant (Variation ID: 8460). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 130 of the FOXC1 protein (p.Leu130Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine.

not provided Uncertain:1

Nov 24, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.59
LIST_S2	Benign	0.0	.;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H
PhyloP100		2.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.8	D;.
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Vest4		0.94
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.93
gMVP		0.96
Mutation Taster		=13/87	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909338; hg19: chr6-1611068;