NM_012186.3(FOXE3):c.289A>G (p.Ile97Val) AND Congenital primary aphakia

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: May 22, 2022
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:: RCV001267882.4

Allele description [Variation Report for NM_012186.3(FOXE3):c.289A>G (p.Ile97Val)]

NM_012186.3(FOXE3):c.289A>G (p.Ile97Val)

Genes:

FOXE3:forkhead box E3 [Gene - OMIM - HGNC]
LINC01389:long intergenic non-protein coding RNA 1389 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p33

Genomic location:

Preferred name:

NM_012186.3(FOXE3):c.289A>G (p.Ile97Val)

HGVS:

NC_000001.11:g.47416604A>G
NG_016192.1:g.5533A>G
NM_012186.3:c.289A>GMANE SELECT
NP_036318.1:p.Ile97Val
NC_000001.10:g.47882276A>G

Protein change:

I97V

Links:

dbSNP: rs774505755

NCBI 1000 Genomes Browser:

rs774505755

Molecular consequence:

NM_012186.3:c.289A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Congenital primary aphakia
Synonyms:: ANTERIOR SEGMENT DYSGENESIS 2; Anterior segment dysgenesis 2, multiple subtypes
Identifiers:: MONDO: MONDO:0012456; MedGen: C1853230; Orphanet: 83461; OMIM: 610256

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001296388	Laboratory of NeuroGenetics and Regenerative Medicine, University of Maryland School of Medicine	no assertion criteria provided	Likely pathogenic	inherited	research
SCV001593182	Human Developmental Genetics Laboratory, Medical College of Wisconsin	no assertion criteria provided	Pathogenic (May 1, 2021)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV002521642	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 22, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20806047, 29878917, 34046667, 32976546, 26995144, 25148791, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001296388

Laboratory of NeuroGenetics and Regenerative Medicine, University of Maryland School of Medicine

no assertion criteria provided

Likely pathogenic

inherited

research

SCV001593182

Human Developmental Genetics Laboratory, Medical College of Wisconsin

no assertion criteria provided

Pathogenic
(May 1, 2021)

germline

research

PubMed (1)
[See all records that cite this PMID]

SCV002521642

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 22, 2022)

germline

clinical testing

PubMed (7)
[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	yes	1	not provided	not provided	1	not provided	research, clinical testing
Asian	inherited	yes	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

Identification of dominant FOXE3 and PAX6 mutations in patients with congenital cataract and aniridia.

Brémond-Gignac D, Bitoun P, Reis LM, Copin H, Murray JC, Semina EV.

Mol Vis. 2010 Aug 22;16:1705-11.

PubMed [citation]

PMID:: 20806047
PMCID:: PMC2927439

Sclerocornea-Microphthalmia-Aphakia Complex: Description of Two Additional Cases Associated With Novel FOXE3 Mutations and Review of the Literature.

Quiroz-Casian N, Chacon-Camacho OF, Barragan-Arevalo T, Nava-Valdez J, Lieberman E, Salgado-Medina A, Navas A, Graue-Hernandez EO, Zenteno JC.

Cornea. 2018 Sep;37(9):1178-1181. doi: 10.1097/ICO.0000000000001655. Review.

PubMed [citation]

PMID:: 29878917

See all PubMed Citations (7)

Details of each submission

From Laboratory of NeuroGenetics and Regenerative Medicine, University of Maryland School of Medicine, SCV001296388.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	1	not provided	not provided	research	not provided

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

From Human Developmental Genetics Laboratory, Medical College of Wisconsin, SCV001593182.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

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

From 3billion, SCV002521642.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (7)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.78; 3Cnet: 0.78). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000983475) and a different missense change at the same codon (p.Ile97Met, ClinVar ID: VCV000935371 / PMID: 29878917) have been reported to be associated with FOXE3 related disorder.The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 20806047, 25148791, 26995144, 34046667) and co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 32976546). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Jun 3, 2022

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