Submissions for variant NM_001453.3(FOXC1):c.380G>A (p.Arg127His)

dbSNP: rs1085307884

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000646226	SCV000767986	pathogenic	Axenfeld-Rieger syndrome type 3	2022-06-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg127 amino acid residue in FOXC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24914578, 28979898; 28979898 24914578). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects FOXC1 function (PMID: 14506133). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FOXC1 protein function. ClinVar contains an entry for this variant (Variation ID: 537389). This missense change has been observed in individual(s) with Axenfeld-Rieger syndrome (PMID: 11740218; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 127 of the FOXC1 protein (p.Arg127His).
Human Developmental Genetics Laboratory, Medical College of Wisconsin	RCV000646226	SCV002538973	pathogenic	Axenfeld-Rieger syndrome type 3	2022-06-23	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV003411525	SCV004110492	pathogenic	FOXC1-related condition	2022-12-15	criteria provided, single submitter	clinical testing	The FOXC1 c.380G>A variant is predicted to result in the amino acid substitution p.Arg127His. This variant has been reported in a mother and son with Axenfeld-Rieger syndrome, and it was determined the variant arose de novo in the mother (Kawase et al. 2001. PubMed ID: 11740218). This variant has also been reported in two unrelated individuals with Axenfeld-Rieger syndrome (Zhang et al. 2021. PubMed ID: 34745210). Different variants that affect this same amino acid residue (p.Arg127Cys and p.Arg127Leu) have been reported in individuals with Axenfeld-Rieger syndrome (Khalil et al. 2017. PubMed ID: 28979898; Du et al. 2016. PubMed ID: 24914578). This c.380G>A (p.Arg127His) variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given the evidence, we interpret c.380G>A (p.Arg127His) as pathogenic.