ClinVar Miner

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

dbSNP: rs796052464
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Total submissions: 4
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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 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.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. ClinVar contains an entry for this variant (Variation ID: 205487). This premature translational stop signal has been observed in individual(s) with clinical features of FOXG1-related conditions (PMID: 24836831, 26993267, 27001178, 30842224). This variant is not present in population databases (gnomAD no frequency). 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.
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).

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