ClinVar

Description

The c.761C>T variant in MYOC is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 254 (p.Pro254Leu).This variant was not found in any population of gnomAD (v2.1.1), meeting the <= 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.925, which met the >= 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 35196929) demonstrated that the Pro254Leu protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. A confirmed de novo proband with juvenile open angle glaucoma was identified (PMID: 27080696), meeting PS2_Moderate. However, as this was the only proband identified, the >= 2 probands threshold required to meet PS4_Supporting was not met. In summary, this variant met the criteria to receive a score of 6 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS2_Moderate, PS3_Moderate, PP3, PM2_Supporting