Submissions for variant NM_005249.5(FOXG1):c.460dup (p.Glu154fs)

dbSNP: rs398124204

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV001507058	SCV001712026	pathogenic	FOXG1 disorder	2021-03-26	reviewed by expert panel	curation	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).
GeneDx	RCV000081281	SCV000241072	pathogenic	not provided	2021-07-22	criteria provided, single submitter	clinical testing	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)
Genetic Services Laboratory, University of Chicago	RCV000170075	SCV000247416	pathogenic	Rett syndrome, congenital variant	2014-10-16	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000081281	SCV000331515	pathogenic	not provided	2015-08-27	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000170075	SCV000484841	pathogenic	Rett syndrome, congenital variant	2016-11-03	criteria provided, single submitter	clinical testing
Invitae	RCV000170075	SCV000824009	pathogenic	Rett syndrome, congenital variant	2023-10-29	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002311627	SCV000845925	pathogenic	Inborn genetic diseases	2016-08-08	criteria provided, single submitter	clinical testing	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.
Undiagnosed Diseases Network, NIH	RCV000170075	SCV001245596	pathogenic	Rett syndrome, congenital variant	2021-01-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000081281	SCV001249822	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000170075	SCV001335519	pathogenic	Rett syndrome, congenital variant		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000170075	SCV002026230	pathogenic	Rett syndrome, congenital variant	2018-01-20	criteria provided, single submitter	clinical testing
3billion	RCV000170075	SCV002058632	pathogenic	Rett syndrome, congenital variant	2022-01-03	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000170075	SCV002808774	pathogenic	Rett syndrome, congenital variant	2022-05-31	criteria provided, single submitter	clinical testing
Duke University Health System Sequencing Clinic, Duke University Health System	RCV000170075	SCV003918989	pathogenic	Rett syndrome, congenital variant	2023-04-20	criteria provided, single submitter	research
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000170075	SCV004244608	pathogenic	Rett syndrome, congenital variant	2023-10-11	criteria provided, single submitter	clinical testing	PVS1, PS4, PM2
PreventionGenetics, part of Exact Sciences	RCV003915077	SCV004732642	pathogenic	FOXG1-related condition	2023-12-11	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000170075	SCV000043980	pathogenic	Rett syndrome, congenital variant	2011-06-01	no assertion criteria provided	literature only
RettBASE	RCV000170075	SCV000222386	pathogenic	Rett syndrome, congenital variant	2012-05-18	no assertion criteria provided	curation
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000170075	SCV001364270	pathogenic	Rett syndrome, congenital variant	2020-02-19	no assertion criteria provided	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000170075	SCV001432381	pathogenic	Rett syndrome, congenital variant		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Strasbourg University Hospital	RCV002274912	SCV002562798	likely pathogenic	Abnormal cerebral morphology		no assertion criteria provided	clinical testing
GenomeConnect - Brain Gene Registry	RCV000170075	SCV004801644	not provided	Rett syndrome, congenital variant		no assertion provided	phenotyping only	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/.