rs672601359

Variant names:

• chr3-138945863-G-GGAGGCGGGGGTGCGGCC
• rs672601359
• NM_023067.4:c.843_859dupGGCCGCACCCCCGCCTC

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.843_859dupGGCCGCACCCCCGCCTC​(p.Pro287ArgfsTer75) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000366 in 1,091,586 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: FOXL2 NM_023067.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17 O:1
• Conservation: PhyloP100: 1.98
• Publications: 11 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 32 pathogenic variants in the truncated region.
• PP5: Variant 3-138945863-G-GGAGGCGGGGGTGCGGCC is Pathogenic according to our data. Variant chr3-138945863-G-GGAGGCGGGGGTGCGGCC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 162045.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.843_859dupGGCCGCACCCCCGCCTC	p.Pro287ArgfsTer75	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.843_859dupGGCCGCACCCCCGCCTC	p.Pro287ArgfsTer75	frameshift_variant	Exon 1 of 1		NM_023067.4	ENSP00000497217.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000366 AC: 4 AN: 1091586 Hom.: 0 Cov.: 31 AF XY: 0.00000193 AC XY: 1 AN XY: 517384

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22782

American (AMR) AF: 0.00 AC: 0 AN: 8602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14214

East Asian (EAS) AF: 0.00 AC: 0 AN: 26214

South Asian (SAS) AF: 0.00 AC: 0 AN: 22252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2958

European-Non Finnish (NFE) AF: 0.00000431 AC: 4 AN: 928620

Other (OTH) AF: 0.00 AC: 0 AN: 44070

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000173310), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Blepharophimosis, ptosis, and epicanthus inversus syndrome Pathogenic:12 Other:1

Jan 01, 2018

Wessex Regional Genetics Laboratory, Salisbury District Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 12, 2010

Center for Medical Genetics Ghent, University of Ghent

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 10, 2022

MGZ Medical Genetics Center

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

- -

-

Suma Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 02, 2018

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Moderate+PS4+PM6+PP1_Strong+PM2_Supporting+PP4 -

Nov 29, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4, PM2, PM6 -

Mar 26, 2024

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Oct 15, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are suggested mechanisms of disease in this gene and are associated with both Type I and II BPES (MIM# 110100). Depending on the assay, both mechanisms have been demonstrated for a given variant (PMID: 18635577, 19515849). (I) 0107 - This gene is associated with autosomal dominant disease with a single family reported for autosomal inheritance (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 12529855). (I) 0205 - Variant is predicted to result in a truncated protein. The premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0604 - Variant is not affecting an established domain, motif, hotspot or informative constraint region. (I) 0701 - Other downstream truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with both Type I and Type II blepharophimosis, epicanthus inversus, and ptosis (BPES) with or without premature ovarian insufficiency, respectively (MIM# 110100) and is considered as a recurrent variant (ClinVar; PMID: 31077882). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Oct 09, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:3

Sep 27, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FOXL2: PVS1, PM2, PS4:Supporting -

Jan 22, 2025

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.Pro287Argfs*75) in the FOXL2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 90 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 individual(s) with blepharophimosis-ptosis-epicanthus inversus syndrome (PMID: 12529855, 31048069). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as 1080-1096dup17. ClinVar contains an entry for this variant (Variation ID: 162045). For these reasons, this variant has been classified as Pathogenic. -

Premature ovarian failure 3 Pathogenic:1

Nov 13, 2023

Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FOXL2-related disorder Pathogenic:1

Jul 17, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FOXL2 c.843_859dup17 variant is predicted to result in a frameshift and premature protein termination (p.Pro287Argfs*75). This variant has been reported as a mutational hotspot in the FOXL2 gene and causative for autosomal dominant blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) type I and II (reported as 1080-1096dup17 in De Baere et al. 2003. PubMed ID: 12529855; Beysen et al. 2008. PubMed ID: 18642388; Chacón-Camacho et al. 2019. PubMed ID: 31048069). In many of the individuals in these reports, the variant was found to have arisen de novo. This variant is classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/162045/). Given the evidence, we interpret FOXL2 c.843_859dup (p.Pro287Argfs*75) as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs672601359; hg19: chr3-138664705;