ClinVar Miner

Submissions for variant NM_005249.5(FOXG1):c.227C>T (p.Pro76Leu)

dbSNP: rs1381438340
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Total submissions: 3
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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 RCV004584226 SCV005068289 likely benign FOXG1 disorder 2024-04-18 reviewed by expert panel curation The p.Pro76Leu variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Pro76Leu variant is found in a patient with an alternate molecular basis of disease (GeneDx internal database) (BP5). Computational analysis prediction tools suggest that the p.Pro76Leu variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Pro76Leu variant in FOXG1 is absent from gnomAD v2.1.1 (PM2_supporting). In the absence of other pathogenic evidence beyond PM2_Supporting, and because this variant has been observed in multiple unaffected individuals and at least two individuals with an alternate molecular diagnosis, the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel has agreed to overrule the PM2_Supporting criterion and classified this variant as likely benign (BS2, BP4, BP5).
Labcorp Genetics (formerly Invitae), Labcorp RCV001321429 SCV001512257 uncertain significance Rett syndrome, congenital variant 2023-04-12 criteria provided, single submitter clinical testing 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. 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 not expected to disrupt FOXG1 protein function. ClinVar contains an entry for this variant (Variation ID: 1021635). This variant has not been reported in the literature in individuals affected with FOXG1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 76 of the FOXG1 protein (p.Pro76Leu).
GeneDx RCV001587343 SCV001823511 likely benign not provided 2019-03-26 criteria provided, single submitter clinical testing

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