Submissions for variant NM_001453.3(FOXC1):c.316C>T (p.Gln106Ter)

dbSNP: rs1057519475

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000416495	SCV000823269	pathogenic	Axenfeld-Rieger syndrome type 3	2018-06-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Different truncations (p.Gln120*, Leu240Valfs*65, p.Ser320Argfs*81) that lie downstream of this variant have been determined to be pathogenic (PMID: 20881294, 16638984, 18498376, 11782474). This suggests that deletion of this region of the FOXC1 protein is causative of disease. Experimental studies have shown that this nonsense change results in decreased protein half-life and increased transactivation (PMID: 25786029). This variant has been observed to segregate with Axenfeld-Rieger syndrome in a family (PMID: 28513611) and has also been observed in individuals affected with Axenfeld-Rieger syndrome (PMID: 20881294) or with bilateral primary congenital glaucoma (PMID: 25786029). ClinVar contains an entry for this variant (Variation ID: 375424). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the FOXC1 gene (p.Gln106*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 448 amino acids (~80%) of the FOXC1 protein.
GeneDx	RCV001567276	SCV001790928	pathogenic	not provided	2021-01-12	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a a hypermorphic effect of the Q106X variant, along with decreased protein stability and protein mis-localization; Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 448 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32224865, 20881294, 25786029, 30514661, 28513611, 28432732)
Genetics and Molecular Pathology, SA Pathology	RCV000416495	SCV000494256	pathogenic	Axenfeld-Rieger syndrome type 3	2014-09-19	no assertion criteria provided	clinical testing	Non-sense codon introduces premature terminating codon (PTC) effecting functional haploinufficiency; clinical significance consistent with FOXC1 PTC variants found upstream and down stream of this position - each regarded as pathogenic in published literature.