ClinVar

Description

The c.1495A>T variant in MYOC is a missense variant predicted to cause substitution of Isoleucine by Phenylalanine at amino acid 499 (p.Ile499Phe). 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 = 0.67, which was neither above nor below the thresholds for PP3 (>= 0.7) or BP4 (<= 0.15), predicting a damaging or benign impact on MYOC function. A previous study (PMID: 16466712) demonstrated that the Ile499Phe protein had 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. 6 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 9328473), which fulfilled PP1_Moderate (5-6 meioses). 2 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 12872267, 9328473), which met PS4_Supporting (>= 2 probands). 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): PS3_Moderate, PP1_Moderate, PS4_Supporting, PM2_Supporting