ClinVar

Description

The c.1139A>C variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Alanine at amino acid 380 (p.Asp380Ala). 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 = 0.97, which met the >= 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Asp380Ala 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. 31 segregations in 6 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 17893668, 9863594, 9832047), which fulfilled PP1_Strong (>= 7 meioses in > 1 family). 7 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 17893668, 9863594, 9832047), which met PS4_Moderate (>= 6 probands). Another missense variant (c.1138G>C, p.Asp380His, Grantham score = 81, ClinVar ID: 7961) in the same codon has been classified as likely pathogenic for juvenile open angle glaucoma by the ClinGen Glaucoma VCEP. The c.1139A>C, p.Asp380Ala variant has a higher Grantham score (= 126) than the previously classified amino acid change, was not predicted to affect splicing as assessed with SpliceAI (<= 0.2), and met PP3, meeting the conditions for PM5_Supporting to apply. In summary, this variant met the criteria to receive a score of 11 and to be classified as pathogenic (pathogenic classification >= 10) 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, PS4_Moderate, PP3, PM2_Supporting, PM5_Supporting.