ClinVar Miner

Submissions for variant NM_005249.5(FOXG1):c.681C>G (p.Asn227Lys)

dbSNP: rs786205012
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel RCV003235088 SCV003933693 uncertain significance FOXG1 disorder 2023-04-14 reviewed by expert panel curation The p.Asn227Lys variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Asn227Lys variant in FOXG1 is absent from gnomAD (PM2_supporting). The p.Asn227Lys variant was observed in an individual with microcephaly, rocking movements, absent speech, epilepsy, bruxism, severe scoliosis, and who is non-ambulatory. However, this individual's parents were not available for segregation analysis and this individual was evaluated once at the age of 13 years old (PMID 19578037) (PP4_not met). In summary, the p.Asn227Lys variant in FOXG1 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM1, PP3, PM2_supporting).
Institute of Human Genetics, University of Leipzig Medical Center RCV000170086 SCV002026255 likely pathogenic Rett syndrome, congenital variant 2018-01-20 criteria provided, single submitter clinical testing
Invitae RCV000170086 SCV002177809 uncertain significance Rett syndrome, congenital variant 2021-09-21 criteria provided, single submitter clinical testing This variant disrupts the p.Asn227 amino acid residue in FOXG1. Other variant(s) that disrupt this residue have been observed in individuals with FOXG1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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: 189623). This missense change has been observed in individual(s) with Rett syndrome, congenital variant (PMID: 19578037). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with lysine at codon 227 of the FOXG1 protein (p.Asn227Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
RettBASE RCV000170086 SCV000222402 uncertain significance Rett syndrome, congenital variant 2010-07-13 no assertion criteria provided curation

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