NM_023067.4(FOXL2):c.855_871dup (p.His291fs) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 15, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000599160.5

Allele description [Variation Report for NM_023067.4(FOXL2):c.855_871dup (p.His291fs)]

NM_023067.4(FOXL2):c.855_871dup (p.His291fs)

Gene:

FOXL2:forkhead box L2 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

3q22.3

Genomic location:

Preferred name:

NM_023067.4(FOXL2):c.855_871dup (p.His291fs)

HGVS:

NC_000003.12:g.138945852_138945868dup17
NC_000003.12:g.138945863_138945879dup
NG_012454.1:g.6273_6289dup
NG_029796.1:g.3630_3646dup
NM_023067.4:c.855_871dupMANE SELECT
NP_075555.1:p.His291fs
LRG_1295t1:c.855_871dup
LRG_1295:g.6273_6289dup
LRG_1295p1:p.His291fs
NC_000003.11:g.138664693_138664694insGGGGGTGCGGCGGAGGC
NC_000003.11:g.138664705_138664721dup
NM_023067.3:c.855_871dup17
p.(His291ArgfsTer71)
p.[His291Argfs*71]

Note:

NCBI staff reviewed the sequence information reported in PubMed 11175783 Fig. 2a to determine the location of this allele on the current reference sequence.

Protein change:

H291fs

Links:

OMIM: 605597.0014; dbSNP: rs797044532

NCBI 1000 Genomes Browser:

rs797044532

Molecular consequence:

NM_023067.4:c.855_871dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000710655	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 29, 2023)	germline	clinical testing	Citation Link,
SCV003525289	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 15, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11175783, 28849110, 31048069, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000710655

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jun 29, 2023)

germline

clinical testing

Citation Link,

SCV003525289

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 15, 2023)

germline

clinical testing

PubMed (4)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.

Crisponi L, Deiana M, Loi A, Chiappe F, Uda M, Amati P, Bisceglia L, Zelante L, Nagaraja R, Porcu S, Ristaldi MS, Marzella R, Rocchi M, Nicolino M, Lienhardt-Roussie A, Nivelon A, Verloes A, Schlessinger D, Gasparini P, Bonneau D, Cao A, Pilia G.

Nat Genet. 2001 Feb;27(2):159-66.

PubMed [citation]

PMID:: 11175783

Identification of a novel FOXL2 mutation in a single family with both types of blepharophimosis‑-ptosis-epicanthus inversus syndrome.

Yang L, Li T, Xing Y.

Mol Med Rep. 2017 Oct;16(4):5529-5532. doi: 10.3892/mmr.2017.7226. Epub 2017 Aug 10.

PubMed [citation]

PMID:: 28849110

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000710655.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Reported previously, using alternate nomenclature of 1092-1108dup17 or c.844_860dup17, in multiple individuals from at least two families affected with blepharophimosis, ptosis, epicanthus inversus syndrome (Crisponi et al., 2001; Yang et al., 2017).; Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28849110, 31048069, 31077882, 32454486, 20184535, 11776388, 12938087, 36338666, 11175783)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003525289.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.His291Argfs*71) in the FOXL2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 86 amino acid(s) of the FOXL2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with blepharophimosis-ptosis-epicanthus inversus syndrome (PMID: 11175783, 28849110, 31048069). It has also been observed to segregate with disease in related individuals. This variant is also known as 1092_1108dup and c.844_860dup17. ClinVar contains an entry for this variant (Variation ID: 4866). For these reasons, this variant has been classified as Pathogenic.

#	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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