Submissions for variant NM_005249.5(FOXG1):c.460del (p.Glu154fs)

dbSNP: rs398124204

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000209851	SCV000265612	pathogenic	Rett syndrome, congenital variant	2016-02-11	criteria provided, single submitter	research
GeneDx	RCV000414502	SCV000490904	pathogenic	not provided	2015-09-16	criteria provided, single submitter	clinical testing	The c.460delG variant in the FOXG1 gene causes a frameshift starting with codon Glutamic acid 154,changes this amino acid to an Arginine residue and creates a premature Stop codon at position 38 of thenew reading frame, denoted p.E154RfsX38. Thisvariant is predicted to cause loss of normal proteinfunction through protein truncation, as the last 336 amino acid residues are replaced with 37 incorrectamino acid residues. Although this variant has not been previously reported to our knowledge, we interpret is as pathogenic.
Invitae	RCV000209851	SCV000952234	pathogenic	Rett syndrome, congenital variant	2022-04-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu154Argfs*38) 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with FOXG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 372563). This variant disrupts a region of the FOXG1 protein in which other variant(s) (p.Gly169Alafs*23) have been determined to be pathogenic (PMID: 24836831, 25356899). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000414502	SCV001762142	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000209851	SCV002026229	pathogenic	Rett syndrome, congenital variant	2018-01-20	criteria provided, single submitter	clinical testing