Submissions for variant NM_005249.5(FOXG1):c.651C>G (p.Tyr217Ter)

dbSNP: rs796052464

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187458	SCV000241051	pathogenic	not provided	2024-12-09	criteria provided, single submitter	clinical testing	Nonsense 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: 24836831, 30842224, 35982159, 34582790, 33057194, 26993267)
Institute of Human Genetics, University of Leipzig Medical Center	RCV001781547	SCV002026254	pathogenic	Rett syndrome, congenital variant	2018-01-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001781547	SCV003442282	pathogenic	Rett syndrome, congenital variant	2021-12-30	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 205487). This sequence change creates a premature translational stop signal (p.Tyr217*) in the FOXG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 273 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 clinical features of FOXG1-related conditions (PMID: 24836831, 26993267, 27001178, 30842224).
Centre for Population Genomics, CPG	RCV004558437	SCV005046867	pathogenic	FOXG1 disorder	2024-05-24	criteria provided, single submitter	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 3 individuals with phenotypes consistent with FOXG1 disorder (PS4_Moderate, PMID: 24836831, PMID: 27001178, PMID: 26993267). This variant is absent from gnomAD (PM2_Supporting).