Submissions for variant NM_005249.5(FOXG1):c.239dup (p.Ala81fs)

gnomAD frequency: 0.00001  dbSNP: rs796052474

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187474	SCV000241067	pathogenic	not provided	2013-09-24	criteria provided, single submitter	clinical testing	c.239dupC: p.Ala81GlyfsX40 (A81Gfsx40) in exon 1 of the FOXG1 gene (NM_005249.3). The normal sequence with the base that is duplicated in braces is: GCCCC{C}GGCA. The c.239dupC mutation in the FOXG1 gene causes a frameshift starting with codon Alanine 81, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 40 of the new reading frame, denoted p.Ala81GlyfsX40. This mutation is predicted to replace the last 409 amino acids of the protein with 39 incorrect amino acids. Although this mutation has not been previously reported to our knowledge, its presence is consistent with a diagnosis of congenital Rett syndrome. The variant is found in EPILEPSY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514003	SCV003461863	pathogenic	Rett syndrome, congenital variant	2022-10-04	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with epilepsy and/or neurodevelopmental disorders (PMID: 29655203). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Ala81Glyfs*40) in the FOXG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 409 amino acid(s) of the FOXG1 protein. ClinVar contains an entry for this variant (Variation ID: 205500). 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.Tyr341*) 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.