ClinVar Miner

Submissions for variant NM_001453.3(FOXC1):c.388C>T (p.Leu130Phe) (rs121909338)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000173256 SCV000224352 uncertain significance not provided 2014-11-24 criteria provided, single submitter clinical testing
Invitae RCV000008980 SCV000647082 likely pathogenic Axenfeld-Rieger syndrome type 3 2016-11-28 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 130 of the FOXC1 protein (p.Leu130Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with Axenfled-Rieger syndrome (PMID: 17197537, 17210863) and it has been shown to arise de novo in one individual (PMID: 17210863). ClinVar contains an entry for this variant (Variation ID: 8460). Experimental evidence suggest this variant results in a severely impaired FOXC1 protein that forms aggregates in the cytoplasm, has reduced localization to the nucleus, reduced DNA binding and reduced transactivation ability (PMID: 19279310, 17013732, 17210863). In addition, expression of this variant in human trabecular meshwork cells shows reduced activity and increased cell death compared to expression of wild type FOXC1 protein (PMID: 24556684). In summary, this is a rare missense change that disrupts protein function in cell culture and has been observed in affected individuals. In the absence of additional genetic data, this variant has been classified as Likely Pathogenic.
OMIM RCV000008980 SCV000029194 pathogenic Axenfeld-Rieger syndrome type 3 2007-01-01 no assertion criteria provided literature only

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