ClinVar

Description

The c.1435T>C variant in MYOC is a missense variant predicted to cause substitution of Tyrosine by Histidine at amino acid 479 (p.Tyr479His). 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 = 0.981, which met the >=0.7 threshold for PP3, predicting a damaging effect on MYOC function. The study reporting functional evidence (PMID: 17615537) demonstrated that the Y479H protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied. Only 1 segregation had been reported for open angle glaucoma (ClinVar: SCV001738398.1), not meeting the >=3 segregations required for PP1. 3 probands with juvenile or primary open angle glaucoma have been reported carrying this variant (PMIDs: 23922489, 17615537 and ClinVar: SCV001738398.1), which met PS4_Supporting (>=2 probands). In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PS4_Supporting, PM2_Supporting