Submissions for variant NM_005249.5(FOXG1):c.506del (p.Gly169fs)

dbSNP: rs1452295073

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000541926	SCV000650053	pathogenic	Rett syndrome, congenital variant	2022-02-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FOXG1 protein in which other variant(s) (p.Tyr400*) have been determined to be pathogenic (PMID: 19564653). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 471470). This premature translational stop signal has been observed in individual(s) with epilepsy, gross motor delays and no language abilities (PMID: 24836831). 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.Gly169Alafs*23) in the FOXG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 321 amino acid(s) of the FOXG1 protein.
Ambry Genetics	RCV001267590	SCV001445772	pathogenic	Inborn genetic diseases	2018-09-28	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV001288608	SCV001475861	pathogenic	not provided	2020-02-20	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
GeneDx	RCV001288608	SCV001791914	pathogenic	not provided	2022-06-06	criteria provided, single submitter	clinical testing	Reported previously in a patient with myoclonic seizures, tonic seizures, and drop seizures (Seltzer et al., 2014); Frameshift variant predicted to result in protein truncation or nonsense mediated decay 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: 27640358, 25356899, 24836831, 30792901, 33644862, 34788679)
Institute of Human Genetics, University of Leipzig Medical Center	RCV000541926	SCV002026233	pathogenic	Rett syndrome, congenital variant	2018-01-20	criteria provided, single submitter	clinical testing
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000541926	SCV002764708	pathogenic	Rett syndrome, congenital variant	2021-12-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000541926	SCV004801467	pathogenic	Rett syndrome, congenital variant	2017-04-28	criteria provided, single submitter	clinical testing	The FOXG1 c.506delG p.(Gly169AlafsTer23) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been identified in a de novo state in individuals with a phenotype consistent with Rett syndrome, congenital variant (Seltzer et al. 2014; Hamdan et al. 2014). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The variant was identified in a de novo state in the proband. Based on the available evidence, the c.506delG p.(Gly169AlafsTer23) variant is classified as pathogenic for Rett syndrome, congenital variant.
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000541926	SCV001432346	pathogenic	Rett syndrome, congenital variant		no assertion criteria provided	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000541926	SCV001787118	pathogenic	Rett syndrome, congenital variant		no assertion criteria provided	clinical testing