ClinVar Miner

Submissions for variant NM_005249.5(FOXG1):c.730C>T (p.Arg244Cys)

dbSNP: rs786205009
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000170082 SCV000770133 pathogenic Rett syndrome, congenital variant 2023-04-17 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FOXG1 function (PMID: 21280142, 22091895). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FOXG1 protein function. ClinVar contains an entry for this variant (Variation ID: 189620). This missense change has been observed in individual(s) with Rett syndrome (PMID: 21280142, 24901346). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 244 of the FOXG1 protein (p.Arg244Cys).
Institute of Human Genetics, University of Leipzig Medical Center RCV000170082 SCV002026257 pathogenic Rett syndrome, congenital variant 2018-01-20 criteria provided, single submitter clinical testing
Centre for Population Genomics, CPG RCV004558432 SCV005046870 likely 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 likely pathogenic. At least the following criteria are met: This variant has been identified as a de novo occurrence in an individual with FOXG1 disorder without confirmation of paternity and maternity (PM6, PMID: 21280142). Occurs in the well-characterized Forkhead functional domain of FOXG1 (PM1). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). Well-established in vitro or in vivo functional studies supportive of a damaging effect on the protein function (PS3_supporting, PMID: 21280142).
RettBASE RCV000170082 SCV000222395 pathogenic Rett syndrome, congenital variant 2011-03-29 no assertion criteria provided curation

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