3-138945851-TGGGGGTGCGGCGGAGGC-TGGGGGTGCGGCGGAGGCGGGGGTGCGGCGGAGGC

Variant names:

• chr3-138945851-T-TGGGGGTGCGGCGGAGGC
• rs797044532
• NM_023067.4:c.855_871dupGCCTCCGCCGCACCCCC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_023067.4(FOXL2):​c.855_871dupGCCTCCGCCGCACCCCC​(p.His291ArgfsTer71) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXL2 NM_023067.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 6.77
• Publications: 10 publications found

Genes affected

FOXL2 (HGNC:1092): (forkhead box L2) This gene encodes a forkhead transcription factor. The protein contains a fork-head DNA-binding domain and may play a role in ovarian development and function. Expansion of a polyalanine repeat region and other mutations in this gene are a cause of blepharophimosis syndrome and premature ovarian failure 3. [provided by RefSeq, Jul 2016]

FOXL2 Gene-Disease associations (from GenCC):

• blepharophimosis, ptosis, and epicanthus inversus syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• premature ovarian failure 3

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 28 pathogenic variants in the truncated region.
• PP5: Variant 3-138945851-T-TGGGGGTGCGGCGGAGGC is Pathogenic according to our data. Variant chr3-138945851-T-TGGGGGTGCGGCGGAGGC is described in ClinVar as Pathogenic. ClinVar VariationId is 4866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXL2	NM_023067.4	c.855_871dupGCCTCCGCCGCACCCCC	p.His291ArgfsTer71	frameshift_variant	Exon 1 of 1	ENST00000648323.1	NP_075555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXL2	ENST00000648323.1	c.855_871dupGCCTCCGCCGCACCCCC	p.His291ArgfsTer71	frameshift_variant	Exon 1 of 1		NM_023067.4	ENSP00000497217.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000277 AC: 3 AN: 1082280 Hom.: 0 Cov.: 30 AF XY: 0.00000195 AC XY: 1 AN XY: 512576

African (AFR) AF: 0.0000443 AC: 1 AN: 22548

American (AMR) AF: 0.00 AC: 0 AN: 8206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14006

East Asian (EAS) AF: 0.00 AC: 0 AN: 25864

South Asian (SAS) AF: 0.00 AC: 0 AN: 21458

European-Finnish (FIN) AF: 0.0000463 AC: 1 AN: 21578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2924

European-Non Finnish (NFE) AF: 0.00000108 AC: 1 AN: 922102

Other (OTH) AF: 0.00 AC: 0 AN: 43594

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Blepharophimosis, ptosis, and epicanthus inversus syndrome Pathogenic:4 Other:1

Nov 03, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2018

Wessex Regional Genetics Laboratory, Salisbury District Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 18, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4, PM2 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 4866). This variant has been previously reported as causative (PMID:31048069). -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Moderate+PM2_Supporting+PS4_Moderate+PP1_Strong+PP4+PS2_Supporting -

not provided Pathogenic:2

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 29, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I Pathogenic:1

Sep 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.8
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs797044532; hg19: chr3-138664693;