NM_001453.3(FOXC1):c.344A>G (p.Tyr115Cys) AND Axenfeld-Rieger syndrome type 3

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 8, 2018
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:: RCV000793577.7

Allele description [Variation Report for NM_001453.3(FOXC1):c.344A>G (p.Tyr115Cys)]

NM_001453.3(FOXC1):c.344A>G (p.Tyr115Cys)

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.344A>G (p.Tyr115Cys)

HGVS:

NC_000006.12:g.1610789A>G
NG_009368.1:g.5344A>G
NM_001453.3:c.344A>GMANE SELECT
NP_001444.2:p.Tyr115Cys
LRG_1245t1:c.344A>G
LRG_1245:g.5344A>G
LRG_1245p1:p.Tyr115Cys
NC_000006.11:g.1611024A>G
NM_001453.2:c.344A>G

Protein change:

Y115C

Links:

dbSNP: rs1581373749

NCBI 1000 Genomes Browser:

rs1581373749

Molecular consequence:

NM_001453.3:c.344A>G - 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
SCV000932938	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 8, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16936096, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000932938

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 8, 2018)

germline

clinical testing

PubMed (2)
[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

Novel mutations of FOXC1 and PITX2 in patients with Axenfeld-Rieger malformations.

Weisschuh N, Dressler P, Schuettauf F, Wolf C, Wissinger B, Gramer E.

Invest Ophthalmol Vis Sci. 2006 Sep;47(9):3846-52. Erratum in: Invest Ophthalmol Vis Sci. 2006 Dec;47(12):5162.

PubMed [citation]

PMID:: 16936096

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000932938.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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. This variant disrupts the p.Tyr115 amino acid residue in FOXC1. Another variant that disrupts this residue has been observed in affected individuals (PMID: 16936096), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in an individual affected with Axenfeld-Rieger syndrome (PMID: 16936096). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with cysteine at codon 115 of the FOXC1 protein (p.Tyr115Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine.

#	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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