Clinical and genetic analysis of Ser341Pro MYOC variant in a Korean family with primary open angle glaucoma

AIM:To report the first discovery of Ser341Pro myocilin(MYOC)variant in Korea and analyze its clinical characteristics and genetic significance.METHODS:Ten family members from three generations participated in this study and received the thorough ophthalmologic examination.Focused exome sequencing on a proband was performed to confirm the target mutations(MYOC c.1021T>C)in the family members,and the direct sequencing was conducted.Variant was analyzed according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology(ACMG/AMP)guidelines.RESULTS:A nucleotide change from thymine to cytosine at c.1021T>C was found in eight family members.Three members diagnosed with primary open angle glaucoma(POAG)were characterized by severe clinical presentations,high intraocular pressure,and poor response to medical treatment(100%of the patient required filtering surgery).On variant analysis by ACMG/AMP guidelines,Ser341Pro is not found in normal population.Multiple computational predictive programs support a deleterious effect of Ser341Pro variant(PoIyPhen 2,SIFT,Mutation Taster).Ser341Pro could be involved in moderate(PM)and supporting(PP)criteria(PM1,PM2,PP2,PP3).Combiningthe criteria,Ser341Pro has a combination of 2 moderate(PM1+PM2)and 2 supporting(PP2+PP3)criteria,which is interpreted to"likely pathogenic".CONCLUSION:The Ser341Pro variant is correlated with severe phenotype of POAG.There are similar clinical aspects to previous studies:autosomal dominant inheritance,incomplete penetrance(62.50%and 66.67%),and proportion of patients requiring trabeculectomy(100%in both study).According to ACMG/AMP guidelines and the previous basic researches,the Ser341Pro variant had a"strong evidence of pathogenicity(PS3)"and then it could be interpreted to“pathogenic(PS3,PM1,PM2,PP2,PP3)”.Additionally,Ser341Pro variant can be reported as"c.1021T>C(p.Ser341Pro)",likely pathogenic,POAG,autosomal dominant”according to guideline.