ClinVar Miner

Submissions for variant NM_005249.5(FOXG1):c.256dup (p.Gln86fs)

dbSNP: rs786205001
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187488 SCV000241082 pathogenic not provided 2023-03-05 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20734096, 30533527, 31316448, 34120799, 31577544, 22968132, 22129046, 26993267, 22739344, 28661489, 35148845)
Labcorp Genetics (formerly Invitae), Labcorp RCV000170074 SCV001203682 pathogenic Rett syndrome, congenital variant 2023-04-17 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: 189613). This variant is also known as c.256_257dupC. This premature translational stop signal has been observed in individual(s) with congenital variant of Rett syndrome (PMID: 20734096). 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 insufficient coverage at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Gln86Profs*35) 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.
CeGaT Center for Human Genetics Tuebingen RCV000187488 SCV001249820 pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000187488 SCV001446572 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center RCV001814085 SCV001755294 pathogenic Abnormality of the nervous system 2021-07-10 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000170074 SCV002026222 pathogenic Rett syndrome, congenital variant 2024-07-16 criteria provided, single submitter clinical testing Criteria applied: PVS1,PS4
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000170074 SCV002575065 pathogenic Rett syndrome, congenital variant criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV000170074 SCV002820305 pathogenic Rett syndrome, congenital variant criteria provided, single submitter clinical testing The frameshift duplication p.Q86Pfs*35 in FOXG1 (NM_005249.5) has been observed in individual(s) with congenital variant of Rett syndrome (Le Guen T et al). The observed variant has been reported to ClinVar as Pathogenic. The p.Q86Pfs*35 variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This pathogenic mutation is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic.
Centre for Population Genomics, CPG RCV004558425 SCV005046891 pathogenic FOXG1 disorder 2024-05-10 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 5 individuals with phenotypes consistent with FOXG1 disorder (PS4). PMID:20734096 PMID:30533527 PMID:22739344 PMID:22129046 PMID:22968132 PMID:31454984 PMID:28661489 PMID:22670136 PMID:26993267 This variant is absent from gnomAD (PM2_Supporting).
RettBASE RCV000170074 SCV000222384 pathogenic Rett syndrome, congenital variant 2013-02-15 no assertion criteria provided curation
PreventionGenetics, part of Exact Sciences RCV004751321 SCV005362608 pathogenic FOXG1-related disorder 2024-04-18 no assertion criteria provided clinical testing The FOXG1 c.256dupC variant is predicted to result in a frameshift and premature protein termination (p.Gln86Profs*35). This variant has been reported as a de novo finding in multiple individuals with congenital variant Rett syndrome (see for example, Le Guen et al. 2011. PubMed ID: 20734096; Takahashi et al. 2011. PubMed ID: 22129046; Khan and Kirmani. 2020. PubMed ID: 31577544). This variant has also been reported in the heterozygous state in an individual with early infantile epileptic encephalopathy (Trump et al. 2016. PubMed ID: 26993267). Another variant resulting in a frameshift at the same codon, c.256del (p.Gln86fs*106), has been classified as pathogenic by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/189612/). Taken together, the c.256dupC (p.Gln86Profs*35) variant is interpreted as pathogenic.

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