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rs1085307884

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001453.3(FOXC1):c.380G>A(p.Arg127His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. 13/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R127L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

FOXC1
NM_001453.3 missense

Scores

17
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 8.86
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001453.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr6-1610825-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 426978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
Variant 6-1610825-G-A is Pathogenic according to our data. Variant chr6-1610825-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 537389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FOXC1NM_001453.3 linkuse as main transcriptc.380G>A p.Arg127His missense_variant 1/1 ENST00000645831.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FOXC1ENST00000645831.2 linkuse as main transcriptc.380G>A p.Arg127His missense_variant 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
LINK: link

Submissions by phenotype

Axenfeld-Rieger syndrome type 3 Pathogenic:2
Pathogenic, criteria provided, single submitterresearchHuman Developmental Genetics Laboratory, Medical College of WisconsinJun 23, 2022- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJun 14, 2022For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg127 amino acid residue in FOXC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24914578, 28979898; 28979898 24914578). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects FOXC1 function (PMID: 14506133). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FOXC1 protein function. ClinVar contains an entry for this variant (Variation ID: 537389). This missense change has been observed in individual(s) with Axenfeld-Rieger syndrome (PMID: 11740218; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 127 of the FOXC1 protein (p.Arg127His). -
FOXC1-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesDec 15, 2022The FOXC1 c.380G>A variant is predicted to result in the amino acid substitution p.Arg127His. This variant has been reported in a mother and son with Axenfeld-Rieger syndrome, and it was determined the variant arose de novo in the mother (Kawase et al. 2001. PubMed ID: 11740218). This variant has also been reported in two unrelated individuals with Axenfeld-Rieger syndrome (Zhang et al. 2021. PubMed ID: 34745210). Different variants that affect this same amino acid residue (p.Arg127Cys and p.Arg127Leu) have been reported in individuals with Axenfeld-Rieger syndrome (Khalil et al. 2017. PubMed ID: 28979898; Du et al. 2016. PubMed ID: 24914578). This c.380G>A (p.Arg127His) variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given the evidence, we interpret c.380G>A (p.Arg127His) as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.59
Cadd
Pathogenic
34
Dann
Pathogenic
1.0
DEOGEN2
Pathogenic
0.99
D;D
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.98
D
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
1.0
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.0
H;H
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-4.7
D;.
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0
D;.
Polyphen
1.0
D;D
Vest4
0.97
MutPred
0.97
Loss of MoRF binding (P = 0.0262);Loss of MoRF binding (P = 0.0262);
MVP
0.99
ClinPred
1.0
D
GERP RS
3.7
Varity_R
0.93
gMVP
0.98

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1085307884; hg19: chr6-1611060; API