rs104893957

Positions:

• chr6-1610837-C-G
• chr6-1610837-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_001453.3(FOXC1):​c.392C>G​(p.Ser131Trp) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FOXC1 NM_001453.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 3.29

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 10 ACMG points.

• PM1: In a DNA_binding_region Fork-head (size 91) in uniprot entity FOXC1_HUMAN there are 27 pathogenic changes around while only 0 benign (100%) in NM_001453.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 6-1610837-C-G is Pathogenic according to our data. Variant chr6-1610837-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 916046.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-1610837-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXC1	NM_001453.3	c.392C>G	p.Ser131Trp	missense_variant	1/1	ENST00000645831.2	NP_001444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXC1	ENST00000645831.2	c.392C>G	p.Ser131Trp	missense_variant	1/1		NM_001453.3	ENSP00000493906	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Axenfeld-Rieger syndrome type 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

-

Trio exome sequencing and subsequent analysis of the genes with the ten highest PEDIA values (PMID: 31164752) revealed a disease-causing missense variant in the FOXC1 gene. The sequencing of exon 1 (NM_001453) revealed a heterozygous base exchange at nucleotide position 392 of the cDNA. The name of the variant is: c.392C> G; p. (Ser131Trp). This replaces the codon for the amino acid serine (TCG) with the codon for the amino acid glycine (TGG). The result was confirmed on a second blood sample using Sanger sequencing. This variant could not be proven in the parents. In population-related databases, the above-mentioned Missense variant not recorded. It is listed once in the phenotype-related databases LOVD and HGMD. In LOVD it is classified as likely pathogenic and in HGMD as disease causing mutation. The mutation prediction programs MutationTaster, SIFT and PolyPhen-2 estimate the variant as pathogenic, the CADD score is 33. The FOXC1 gene codes for a transcription factor. The detected variant is in a conserved position of the DNA binding domains ("fork-head" domains). The ACMG classification is pathogenic (classification 5: PS2 PS1 PM2 PM5 PP3 PP4). Certain variants in the FOXC1 gene can lead to the autosomal dominant hereditary Axenfeld-Rieger syndrome type 3 (OMIM # 602482), in which there are characteristically malformations of the eye that are often combined with other malformations / symptoms: facial dysmorphia with hypertelorism and midface hypoplasia, heart defects, hearing loss, hypospadias, increased periumbilical skin, hypoplasia of the vermis cerebelli, tooth abnormalities and anal stenoses. The detected variant in the FOXC1 gene has already been described in a patient with Axenfeld Rieger syndrome type 3 with iris hypoplasia, congenital scoliosis and tooth abnormalities (PMID # 20881294). A variant at the same amino acid position p. (Ser131Leu) was also published as causative for Axenfeld-Rieger syndrome type 3 with glaucoma (PMID # 9620769). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H;H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.7	D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.92		Gain of MoRF binding (P = 0.0652);Gain of MoRF binding (P = 0.0652);
MVP		1.0
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.95
gMVP		0.99

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: rs104893957; hg19: chr6-1611072;