ClinVar Miner

Submissions for variant NM_023067.4(FOXL2):c.644A>G (p.Tyr215Cys)

dbSNP: rs1057516168
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000408786 SCV000484878 pathogenic Blepharophimosis, ptosis, and epicanthus inversus syndrome 2016-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000523621 SCV000617545 pathogenic not provided 2019-12-13 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18604817, 22312189, 30029625, 19515849, 15257268, 18484667, 27283035, 30234390)
Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud RCV000523621 SCV002098085 likely pathogenic not provided 2022-02-02 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003392224 SCV004119824 pathogenic FOXL2-related condition 2023-10-11 criteria provided, single submitter clinical testing The FOXL2 c.644A>G variant is predicted to result in the amino acid substitution p.Tyr215Cys. This variant has been reported as segregating with disease in a five generation kindred with blepharophimosis-ptosis-epicanthus inversus syndrome (Kumar et al. 2004. PubMed ID: 15257268). This variant has also been reported in a sporadic case of BPES (Wang et al. 2022. PubMed ID: 36338666). A functional study using protein expression in cell culture found that the p.Tyr215Cys substitution causes protein aggregation (Dipietromaria et al. 2009. PubMed ID: 19515849). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given all the evidence, we interpret this variant as pathogenic.

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