ClinVar

Description

The c.1267A>G variant in MYOC is a missense variant predicted to cause substitution of Lysine by Glutamic Acid at amino acid 423 (p.Lys423Glu). 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 = 0.876, which met the >= 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Lys423Glu 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. 80 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 12860809, 9697688), which fulfilled PP1_Strong (>=7 meioses in >1 family). 4 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 30484747, 12189160, 12860809, 9697688), which met PS4_Supporting (>= 2 probands). In summary, this variant met the criteria to receive a score of 9 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): PP1_Strong, PS3_Moderate, PP3, PS4_Supporting, PM2_Supporting