NM_001453.3(FOXC1):c.403T>A (p.Cys135Ser) AND Axenfeld-Rieger syndrome type 3

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 8, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003509111.2

Allele description [Variation Report for NM_001453.3(FOXC1):c.403T>A (p.Cys135Ser)]

NM_001453.3(FOXC1):c.403T>A (p.Cys135Ser)

Gene:

FOXC1:forkhead box C1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p25.3

Genomic location:

Preferred name:

NM_001453.3(FOXC1):c.403T>A (p.Cys135Ser)

HGVS:

NC_000006.12:g.1610848T>A
NG_009368.1:g.5403T>A
NG_175047.1:g.276T>A
NM_001453.3:c.403T>AMANE SELECT
NP_001444.2:p.Cys135Ser
LRG_1245t1:c.403T>A
LRG_1245:g.5403T>A
LRG_1245p1:p.Cys135Ser
NC_000006.11:g.1611083T>A

Protein change:

C135S

Molecular consequence:

NM_001453.3:c.403T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Axenfeld-Rieger syndrome type 3 (RIEG3)
Synonyms:: Axenfeld-rieger anomaly with or without cardiac defects and/or sensorineural hearing loss; Rieger syndrome type 3; Anterior chamber cleavage syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011233; MedGen: C2678503; Orphanet: 782; OMIM: 602482

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004299336	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18708620, 27804176, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004299336

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 8, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The transcription factor gene FOXC1 exhibits a limited role in primary congenital glaucoma.

Chakrabarti S, Kaur K, Rao KN, Mandal AK, Kaur I, Parikh RS, Thomas R.

Invest Ophthalmol Vis Sci. 2009 Jan;50(1):75-83. doi: 10.1167/iovs.08-2253. Epub 2008 Aug 15.

PubMed [citation]

PMID:: 18708620

Comparison of Bioinformatics Prediction, Molecular Modeling, and Functional Analyses of FOXC1 Mutations in Patients with Axenfeld-Rieger Syndrome.

Seifi M, Footz T, Taylor SA, Walter MA.

Hum Mutat. 2017 Feb;38(2):169-179. doi: 10.1002/humu.23141. Epub 2016 Nov 21.

PubMed [citation]

PMID:: 27804176

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004299336.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant has not been reported in the literature in individuals affected with FOXC1-related conditions. This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 135 of the FOXC1 protein (p.Cys135Ser). This variant is not present in population databases (gnomAD no frequency). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Cys135 amino acid residue in FOXC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18708620, 27804176). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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