Genetic Variant FOXG1:p.Gln86ProfsTer35 (chr14-28767528-G-GC) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_005249.5(FOXG1):c.256dupC(p.Gln86ProfsTer35) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000044 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FOXG1
NM_005249.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: -0.607

Variant links:

Genes affected

FOXG1 (HGNC:3811): (forkhead box G1) This locus encodes a member of the fork-head transcription factor family. The encoded protein, which functions as a transcriptional repressor, is highly expressed in neural tissues during brain development. Mutations at this locus have been associated with Rett syndrome and a diverse spectrum of neurodevelopmental disorders defined as part of the FOXG1 syndrome. This gene is disregulated in many types of cancer and is the target of multiple microRNAs that regulate the proliferation of tumor cells. [provided by RefSeq, Jul 2020]

FOXG1 links:

LINC01551 (HGNC:19828): (long intergenic non-protein coding RNA 1551)

LINC01551 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 59 pathogenic variants in the truncated region.

PP5

Variant 14-28767528-G-GC is Pathogenic according to our data. Variant chr14-28767528-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 189613.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
FOXG1	NM_005249.5 link	c.256dupC	p.Gln86ProfsTer35	frameshift_variant	Exon 1 of 1	ENST00000313071.7	NP_005240.3	P55316

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOXG1	ENST00000313071.7 link	c.256dupC	p.Gln86ProfsTer35	frameshift_variant	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3	P55316
FOXG1	ENST00000706482.1 link	c.256dupC	p.Gln86ProfsTer35	frameshift_variant	Exon 2 of 2			ENSP00000516406.1	P55316
LINC01551	ENST00000675861.1 link	n.374+1522dupC		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

146708

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

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0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

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0.00

Gnomad SAS

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0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000438

AC:

AN:

913400

Hom.:

Cov.:

AF XY:

0.00000232

AC XY:

AN XY:

430174

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000872

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000371

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

146708

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71344

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

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0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rett syndrome, congenital variant

Pathogenic:5

Feb 15, 2013

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frameshift duplication p.Q86Pfs*35 in FOXG1 (NM_005249.5) has been observed in individual(s) with congenital variant of Rett syndrome (Le Guen T et al). The observed variant has been reported to ClinVar as Pathogenic. The p.Q86Pfs*35 variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This pathogenic mutation is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic. -

Jul 16, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS4 -

Apr 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 189613). This variant disrupts a region of the FOXG1 protein in which other variant(s) (p.Ser472Ilefs*15) have been determined to be pathogenic (Invitae). 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. This variant is also known as c.256_257dupC. This sequence change creates a premature translational stop signal (p.Gln86Profs*35) in the FOXG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 404 amino acid(s) of the FOXG1 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 congenital variant of Rett syndrome (PMID: 20734096). In at least one individual the variant was observed to be de novo. -

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 05, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 20734096, 30533527, 31316448, 34120799, 31577544, 22968132, 22129046, 26993267, 22739344, 28661489, 35148845) -

Abnormality of the nervous system

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FOXG1 disorder

Pathogenic:1

May 10, 2024

Centre for Population Genomics, CPG

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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:20734096 PMID:30533527 PMID:22739344 PMID:22129046 PMID:22968132 PMID:31454984 PMID:28661489 PMID:22670136 PMID:26993267 This variant is absent from gnomAD (PM2_Supporting). -

FOXG1-related disorder

Pathogenic:1

Apr 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FOXG1 c.256dupC variant is predicted to result in a frameshift and premature protein termination (p.Gln86Profs*35). This variant has been reported as a de novo finding in multiple individuals with congenital variant Rett syndrome (see for example, Le Guen et al. 2011. PubMed ID: 20734096; Takahashi et al. 2011. PubMed ID: 22129046; Khan and Kirmani. 2020. PubMed ID: 31577544). This variant has also been reported in the heterozygous state in an individual with early infantile epileptic encephalopathy (Trump et al. 2016. PubMed ID: 26993267). Another variant resulting in a frameshift at the same codon, c.256del (p.Gln86fs*106), has been classified as pathogenic by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/189612/). Taken together, the c.256dupC (p.Gln86Profs*35) variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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Calibrated prediction

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Splicing

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Calibrated prediction

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SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

14-28767528-GC-GCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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