Submissions for variant NM_005249.5(FOXG1):c.460G>T (p.Glu154Ter)

dbSNP: rs1057520780

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000429306	SCV000517426	pathogenic	not provided	2021-09-27	criteria provided, single submitter	clinical testing	Identified in a patient with a neurodevelopmental disorder (Lindy et al., 2018); Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29655203, 34284163)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002524860	SCV003461878	pathogenic	Rett syndrome, congenital variant	2022-10-10	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 379912). 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. This premature translational stop signal has been observed in individual(s) with clinical features of congenital / atypical Rett syndrome (PMID: 29655203, 34284163). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu154*) in the FOXG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 336 amino acid(s) of the FOXG1 protein.
PreventionGenetics, part of Exact Sciences	RCV003392239	SCV004121602	pathogenic	FOXG1-related disorder	2022-09-21	criteria provided, single submitter	clinical testing	The FOXG1 c.460G>T variant is predicted to result in premature protein termination (p.Glu154*). This variant was reported in an individual with epilepsy and/or neurodevelopmental disorders (Lindy et al. 2018. PubMed ID: 29655203) and in a fetus with brain morphological abnormalities (Wilpert et al. 2021. PubMed ID: 34284163). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in FOXG1 are expected to be pathogenic. This variant is interpreted as pathogenic.