Submissions for variant NM_001453.3(FOXC1):c.718_719del (p.Leu240fs)

dbSNP: rs1057519480

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000416550	SCV000647085	pathogenic	Axenfeld-Rieger syndrome type 3	2017-05-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. A different truncation downstream of this variant (c.816_817delinsG) has been determined to be pathogenic (PMID: 20881294). This suggests that deletion of this region of the FOXC1 protein is causative of disease. This variant has been reported to be de novo in an individual affected with Axenfeld-Rieger syndrome with developmental glaucoma (PMID: 16638984). ClinVar contains an entry for this variant (Variation ID: 375429). While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change results in a premature translational stop signal in the FOXC1 gene (p.Leu240Valfs*65). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 314 amino acids of the FOXC1 protein.
Human Developmental Genetics Laboratory, Medical College of Wisconsin	RCV000416550	SCV002538959	pathogenic	Axenfeld-Rieger syndrome type 3	2022-06-23	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004594054	SCV002767748	pathogenic	Anterior segment dysgenesis 3	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with Axenfeld-Rieger syndrome, type 3 (MIM #602482), anterior segment dysgenesis 3 (MIM #601631), congenital glaucoma (PMID: 31836490) and juvenile open angle glaucoma (PMID: 31836490). While loss of function has been functionally proven for some missense variants, the evidence for truncating variants is currently limited (PMID: 19513095). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variants in FOXC1 have been reported to demonstrate interfamilial and intrafamilial expressivity (PMIDs: 19513095; 31836490). 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0701 - Other protein-truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are greater than four protein-truncating variants located downstream of this variant (ClinVar; Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in ClinVar and has been observed as de novo in an internal VCGS patient and in an unrelated individual in the literature with FOXC1-related features (ClinVar, PMID: 16638984). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genetics and Molecular Pathology, SA Pathology	RCV000416550	SCV000494261	pathogenic	Axenfeld-Rieger syndrome type 3	2015-06-11	no assertion criteria provided	clinical testing	Frame-shift introducing 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.