14-28767732-CGG-CGGG
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS2PVS1PM2_SupportingPS4
This summary comes from the ClinGen Evidence Repository: The p.Glu154Glyfs variant in FOXG1 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Glu154Glyfs variant in FOXG1 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with FOXG1 disorder (PMID 19806373, 28661489, Internal database-GeneDx) (PS2_VS). The p.Glu154Glyfs variant has also has been observed in at least 10 other individuals with FOXG1 disorder (PMID 19806373, 24836831, 26344814, 28851325, 29595814, 29655203, 29322350, 28661489) (PS4). The p.Glu154Glyfs variant in FOXG1 is absent from gnomAD (PM2_supporting). In summary, the p.Glu154Glyfs variant in FOXG1 is classified as Pathogenic for FOXG1 disorder based on the ACMG/AMP criteria (PVS1, PS2_VS, PS4, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA199435/MONDO:0100040/016
Frequency
Consequence
NM_005249.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FOXG1 | ENST00000313071.7 | c.460dupG | p.Glu154GlyfsTer301 | frameshift_variant | Exon 1 of 1 | 6 | NM_005249.5 | ENSP00000339004.3 | ||
| FOXG1 | ENST00000706482.1 | c.460dupG | p.Glu154GlyfsTer301 | frameshift_variant | Exon 2 of 2 | ENSP00000516406.1 | ||||
| LINC01551 | ENST00000675861.1 | n.374+1726dupG | intron_variant | Intron 1 of 3 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000158 AC: 2AN: 1268600Hom.: 0 Cov.: 34 AF XY: 0.00000159 AC XY: 1AN XY: 628114
GnomAD4 genome
ClinVar
Submissions by phenotype
Rett syndrome, congenital variant Pathogenic:15Other:1
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PVS1, PS4, PM2 -
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A known frameshift variant, c.460dup p.(Glu154GlyfsTer301) in exon 1 of FOXG1 (NM_005249.5) (Kortüm F et al., 2011; Mitter D et al., 2018; ClinVar ID: VCV000095268.62) was observed in heterozygous state in the proband. On segregation analysis, this variant was absent in his parents. The variant c.460dup has been observed in two individuals in heterozygous state in the gnomAD (v4.1.0) population database (allele frequency: 0.000001417), and absent in our in-house data of 3502 exomes. This variant is predicted to cause a premature stop codon that leads to a truncated or absent FOXG1 protein. -
Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S).The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000095268, PMID:19806373). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 24836831, 19806373, 29595814, 28851325, 29322350, 26344814, 29655203, 28661489, PS4_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). The same variant was also reported as de novo in one or more affected individuals (PMID: 19806373, 28661489, PS2_VS). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
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This sequence change creates a premature translational stop signal (p.Glu154Glyfs*301) in the FOXG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 336 amino acid(s) of the FOXG1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with FOXG1-related disorders (PMID: 19806373, 21441262, 24836831, 26344814, 28661489, 28851325). In at least one individual the variant was observed to be de novo. This variant is also known as c.454dupG. ClinVar contains an entry for this variant (Variation ID: 95268). For these reasons, this variant has been classified as Pathogenic. -
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Variant classified as Pathogenic and reported on 04-09-2021 by Prevention Genetics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
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not provided Pathogenic:3
Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19806373, 25131622, 32472944, 23757202, 29322350, 28661489, 24836831, 33096386, 28851325, 26344814, 29595814, 29655203, 21441262, 26364767, 22190898) -
FOXG1: PS2, PVS1:Strong, PS4:Moderate -
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FOXG1 disorder Pathogenic:2
The p.Glu154Glyfs variant in FOXG1 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Glu154Glyfs variant in FOXG1 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with FOXG1 disorder (PMID 19806373, 28661489, Internal database-GeneDx) (PS2_VS). The p.Glu154Glyfs variant has also has been observed in at least 10 other individuals with FOXG1 disorder (PMID 19806373, 24836831, 26344814, 28851325, 29595814, 29655203, 29322350, 28661489) (PS4). The p.Glu154Glyfs variant in FOXG1 is absent from gnomAD (PM2_supporting). In summary, the p.Glu154Glyfs variant in FOXG1 is classified as Pathogenic for FOXG1 disorder based on the ACMG/AMP criteria (PVS1, PS2_VS, PS4, PM2_supporting). -
This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with FOXG1 disorder (PS4).PMID:33096386 ,PMID:26364767 , PMID:22739344 , PMID:26344814 , PMID:31454984 , PMID:30533527 , Variation ID: 95268 This variant is absent from gnomAD v4 (PM2_Supporting). -
Inborn genetic diseases Pathogenic:1
The c.460dupG pathogenic mutation, located in coding exon 1 of the FOXG1 gene, results from a duplication of G at nucleotide position 460, causing a translational frameshift with a predicted alternate stop codon. This mutation was originally reported as de novo in a female patient with significant neurological impairment, marked axial hypotonia, peripheral spasticity, no language, convergent strabismus, and obvious repetitive hand movements (Bahi-Buisson N et al. Neurogenetics, 2010 May;11:241-9). This mutation has been identified in multiple additional patients with clinical features of congenital or classic Rett syndrome (Kortüm F et al. J. Med. Genet., 2011 Jun;48:396-406; Van der Aa N et al. Mol Syndromol, 2011 Sep;1:290-293; Seltzer LE et al. Epilepsia, 2014 Aug;55:1292-300). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Abnormal cerebral morphology Pathogenic:1
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FOXG1-related disorder Pathogenic:1
The FOXG1 c.460dupG variant is predicted to result in a frameshift and premature protein termination (p.Glu154Glyfs*301). This variant has been repeatedly reported to occur in individuals with Rett syndrome (Bahi-Buisson et al 2010. PubMed ID: 19806373; Seltzer LE et al 2014. PubMed ID: 24836831; Cellini E et al 2015. PubMed ID: 26344814; Zhang Q et al 2017. PubMed ID: 28851325). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. The ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel has interpreted this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/95268/). Frameshift variants in FOXG1 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at