3-138945918-CG-CGG
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_023067.4(FOXL2):c.804dupC(p.Gly269ArgfsTer265) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000844 in 1,184,694 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_023067.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 8.44e-7 AC: 1AN: 1184694Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 571600
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Blepharophimosis, ptosis, and epicanthus inversus syndrome Pathogenic:2Other:1
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Blepharophimosis, ptosis, and epicanthus inversus syndrome;C1837008:Premature ovarian failure 3 Pathogenic:2
PVS1_Strong+PM2_Supporting+PS4+PM6+PP4+PP1_Strong -
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not provided Pathogenic:2
This sequence change creates a premature translational stop signal (p.Gly269Argfs*265) in the FOXL2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 108 amino acid(s) of the FOXL2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with blepharophimosis, ptosis, and epicanthus inversus syndrome (PMID: 17277738). ClinVar contains an entry for this variant (Variation ID: 4858). This variant disrupts a region of the FOXL2 protein in which other variant(s) (p.Ala304Hisfs*52) have been determined to be pathogenic (PMID: 11468277). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
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Inborn genetic diseases Pathogenic:1
The c.804dupC (p.G269Rfs*265) alteration, located in exon 1 (coding exon 1) of the FOXL2 gene, consists of a duplication of C at position 804, causing a translational frameshift with a predicted alternate stop codon after 265 amino acids. Frameshifts are typically deleterious in nature; however, because FOXL2 is a single-exon gene this alteration is not expected to trigger nonsense-mediated mRNA decay and an altered protein could still be expressed. This frameshift impacts the last 29% of the native protein and results in the elongation of the protein by 157 amino acids. The exact functional impact of these altered amino acids is unknown at this time. The FOXL2 c.804dupC alteration was flagged as a low confidence call in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES), some of which also had a family history of BPES, and this variant was shown to segregate with disease in one family (Wang, 2007; Kaur, 2011; Bunyan, 2019). Additionally, this variant was detected de novo in one female with premature ovarian insufficiency, narrow palpebral fissures, and polycystic ovary morphology (Shen, 2021). Based on the available evidence, this alteration is classified as pathogenic. -
BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II Pathogenic:1
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BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at