ClinVar Miner

Submissions for variant NM_005249.5(FOXG1):c.577G>A (p.Ala193Thr)

dbSNP: rs786205005
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000170078 SCV000650054 pathogenic Rett syndrome, congenital variant 2017-06-08 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported to be de novo in individuals affected with FOXG1-related disorders including Rett syndrome (PMID:  22190898, 27029630, 24836831).  ClinVar contains an entry for this variant (Variation ID: 189616). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 193 of the FOXG1 protein (p.Ala193Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine.
Ambry Genetics RCV000624178 SCV000741670 pathogenic Inborn genetic diseases 2016-07-05 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000170078 SCV002026246 likely pathogenic Rett syndrome, congenital variant 2018-01-20 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV000170078 SCV004048384 likely pathogenic Rett syndrome, congenital variant criteria provided, single submitter clinical testing The missense variant p.Ala193Thr in FOXG1 has been reported to be de novo in individuals affected with FOXG1-related disorders including Rett syndrome (Van der Aa N et. al., 2011). The p.Ala193Thr variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been submitted to ClinVar as Pathogenic/Likely Pathogenic, but no details are available for independent assessment. The amino acid Ala at position 193 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The amino acid change p.Ala193Thr in FOXG1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Centre for Population Genomics, CPG RCV004558428 SCV005046884 pathogenic FOXG1 disorder 2024-05-30 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: This variant has been identified as a de novo occurrence in at least 2 individuals with FOXG1 disorder, without confirmation of paternity and maternity (PM6_Strong). PMID: 22190898, PMID: 28661489 Has been observed in at least 5 individuals with phenotypes consistent with FOXG1 disorder (PS4). PMID:22190898 PMID:27029630 PMID:31199603 PMID:24766421 PMID:26344814 PMID:18571142 PMID:21441262 PMID:28661489 PMID:24836831 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).
RettBASE RCV000170078 SCV000222389 pathogenic Rett syndrome, congenital variant 2012-05-18 no assertion criteria provided curation

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