14-28767528-GC-G

Position:

• chr14-28767528-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PP4 PM6_Strong PM2_Supporting PS4_Moderate PVS1

This summary comes from the ClinGen Evidence Repository: The p.Gln86Argfs 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.Gln86Argfs variant in FOXG1 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with FOXG1 disorder (PMID 22739344, 2634418) (PM6_strong, PP4). This variant has been observed in at least 3 other individuals with FOXG1 disorder (PMID 22739344, 26344814) (PS4_moderate). The c.256delC variant in FOXG1 is absent from gnomAD (PM2_supporting). In summary, the p.Gln86Argfs variant in FOXG1 is classified as Pathogenic for FOXG1 disorder based on the ACMG/AMP criteria (PVS1, PM6_strong, PS4_moderate, PM2_supporting, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA199433/MONDO:0100040/016

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: FOXG1 NM_005249.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: -0.607

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]

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

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.256del	p.Gln86ArgfsTer106	frameshift_variant	1/1	ENST00000313071.7	NP_005240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXG1	ENST00000313071.7	c.256del	p.Gln86ArgfsTer106	frameshift_variant	1/1		NM_005249.5	ENSP00000339004	P1
FOXG1	ENST00000706482.1	c.256del	p.Gln86ArgfsTer106	frameshift_variant	2/2			ENSP00000516406	P1
LINC01551	ENST00000675861.1	n.374+1522del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000985 AC: 9 AN: 913394 Hom.: 0 Cov.: 16 AF XY: 0.0000139 AC XY: 6 AN XY: 430168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000256

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000174

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000743

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome, congenital variant Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	-	Criteria applied: PVS1,PS2,PS4; dedicated FOXG1 criteria, Version 3.0.0 -
Pathogenic, no assertion criteria provided	curation	RettBASE	Feb 15, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 30, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Heterozygous Frameshift variant c.250delC in Exon 1 of the FOXG1 gene that results in the amino acid substitution p.Gln86fs*106 was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic(Variant ID 189612). This variant has been previously reported by Celini et al., 2016. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 11, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189612). This premature translational stop signal has been observed in individual(s) with FOXG1-related conditions (PMID: 22739344, 26344814). In at least one individual the variant was observed to be de novo. 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 sequence change creates a premature translational stop signal (p.Gln86Argfs*106) 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. -

FOXG1 disorder Pathogenic:3

Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 25, 2021	The p.Gln86Argfs 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.Gln86Argfs variant in FOXG1 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with FOXG1 disorder (PMID 22739344, 2634418) (PM6_strong, PP4). This variant has been observed in at least 3 other individuals with FOXG1 disorder (PMID 22739344, 26344814) (PS4_moderate). The c.256delC variant in FOXG1 is absent from gnomAD (PM2_supporting). In summary, the p.Gln86Argfs variant in FOXG1 is classified as Pathogenic for FOXG1 disorder based on the ACMG/AMP criteria (PVS1, PM6_strong, PS4_moderate, PM2_supporting, PP4). -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Mar 13, 2024	The heterozygous p.Gln86ArgfsTer106 variant in FOXG1 was identified by our study in one individual with congenital fibrosis of the extraocular muscles, gastroesophageal reflux,and fine motor delay, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). We believe this is a phenotype expansion for FOXG1-related disorders. The p.Gln86ArgfsTer106 variant in FOXG1 has been previously reported in 9 unrelated individuals with FOXG1-related disease (PMID: 32860008, PMID: 33106377, PMID: 30533527, PMID: 31316448, PMID: 28661489, PMID: 31238879, PMID: 22739344, PMID: 26344814). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 5 individuals with confirmed paternity and maternity (PMID: 30533527, PMID: 28661489, PMID: 22739344, PMID: 26344814) and is assumed de novo in one individual, but maternity and paternity have not been confirmed (PMID: 31316448). The phenotype of individuals heterozygous for this variant is highly specific for FOXG1-related disease based on the presence of core phenotypic consistent with disease, as defined in the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel (PMID: 31238879, PMID: 26344814, PMID: 31316448, PMID: 28661489, PMID: 22739344). This variant has also been reported in ClinVar (Variation ID: 189612) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 86 and leads to a premature termination codon 106 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the FOXG1 gene is an established disease mechanism in FOXG1-related disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FOXG1-related disease. ACMG/AMP Criteria applied: PVS1, PS2_VeryStrong, PS4, PM2_Supporting, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	May 10, 2024	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:22739344 PMID:26344814 PMID:31316448 PMID:30533527 PMID:28661489 ClinVar Variation ID: 189612 This variant is absent from gnomAD v4 (PM2_Supporting). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2022

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: 26344814, 22739344, 28661489, 31316448, 31019990, 30533527, 34964776, 33106377, 32860008, 31238879) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs786205001; hg19: chr14-29236734;