ClinVar

Description

The c.1138G>C variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Histidine at amino acid 380 (p.Asp380His). 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 = 0.965, which met the >= 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 35196929) demonstrated that the Asp380His 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. 9 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 17499207), which fulfilled PP1_Moderate (>= 5 meioses in >= 1 family, but not the >= 7 meioses in > 1 family for the strong criterion). Only 1 proband with JOAG had been reported (PMID: 17499207), not meeting the >= 2 probands threshold required to meet PS4_Supporting. 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, PP3, PM2_Supporting.